High penetration prodrug compositions of retinoids and retinoid-related compounds

ABSTRACT

The invention provides compositions of novel high penetration compositions (HPC) or high penetration prodrugs (HPP) of retinoids and retinoid-related compounds, which are capable of crossing biological barriers with high penetration efficiency. The HPPs are capable of being converted to parent active drugs or drug metabolites after crossing the biological barrier and thus can render treatments for the conditions that the parent drugs or metabolites can. Additionally, the HPPs are capable of reaching areas that parent drugs may not be able to access or to render a sufficient concentration at the target areas and therefore render novel treatments. The HPPs can be administered to a subject through various administration routes, e.g., locally delivered to an action site of a condition with a high concentration or systematically administered to a biological subject and enter the general circulation with a faster rate.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a divisional of U.S. patent application Ser.No. 12/503,739, filed Jul. 15, 2009, which is a continuation-in-partapplication of International Application PCT/IB2007/050122, filed Jan.15, 2007 and published Jul. 24, 2008 with International PublicationNumber WO2008/087493, which is incorporated herein by reference in itsentirety.

FIELD OF THE INVENTION

This invention relates to the field of pharmaceutical compositionscapable of penetrating one or more biological barriers and methods ofusing the pharmaceutical compositions for preventing, diagnosing and/ortreating condition or disease in human and animals that are treatable byretinoid or retinoid-related compounds. The invention also relates tomethods of using the pharmaceutical compositions for screening new drugcandidates and methods of using the pharmaceutical compositions fordiagnosing a condition in a biological subject.

BACKGROUND OF THE INVENTION

Retinoids are a class of compounds that comprise a four-isoprenoid unitin their molecular structures. Examples of retinoids include retinol(vitamin A), retinal, retiferol, tretinoin (all-trans-retinoic acid,e.g. retinoic acid, Retin-A), isotretinoin, alitretinoin (9-cis-retinoicacid), etretinate, acitretin, tazarotene, bexarotene and Adapalene.

Retinoids and retinoid-related compounds have important and diversefunctions in a biological system, and have been used to treat variousconditions such as acne, photoaging, psoriasis, ichthyosis, hair lossand tumor. However, time and/or dosage related adverse effects have beenalso reported. Examples of adverse effects of retinoids andretinoid-related compounds include painful tender swellings on the longbones, anorexia, skin lesions, hair loss, hepatosplenomegaly,papilloedema, bleeding, general malaise, pseudotomor cerebri and evendeath.

One alternative method of drug administration is topical delivery.Topical drug delivery has several advantages. This method avoidsinactivation of a drug caused by first pass metabolism in the liver andgastro-intestinal tract. It also provides local delivery of appropriateconcentrations of a drug to the intended site of action without systemicexposure. Fishman (Fishman; Robert, U.S. Pat. No. 7,052,715) indicatedthat an additional problem associated with oral medications, is that theconcentration levels which must be achieved in the bloodstream must besignificant in order to effectively treat distal areas of pain,inflammation, or infection. These levels are often much higher thanwould be necessary if the drugs were accurately delivered to theparticular site of pain or injury. For most of retinoids, topicaladministration cannot deliver an effective therapeutic level.

Therefore, a need exists in the art for novel compositions that arecapable of being delivered efficiently and effectively to the actionsite of a condition (e.g., a disease) to prevent, reduce or treatconditions as well as minimize adverse side effects.

SUMMARY OF THE INVENTION

One aspect of the invention is directed to a high penetration prodrug(HPP) or high penetration composition (HPC) comprising a functional unitcovalently linked to a transportational unit through a linker. The terms“HPP” and “HPC” are used alone or together herein and areinterchangeable unless specifically noted.

In certain embodiments, a functional unit of a HPP or HPC comprises amoiety of an agent, wherein the efficient and effective delivery of theagent to a biological subject and/or transportation of the agent acrossone or more biological barriers are/is desired.

In certain embodiments, a functional unit may be hydrophilic,lipophilic, or amphiphilic (i.e., both hydrophilic and lipophilic). Forexample, the lipophilic nature of a function unit may be inherent orachieved by converting the hydrophilic moieties of a functional unit tolipophilic moieties. In certain embodiments, a carboxyl group, aminogroup, guanidine group or other hydrophilic group of a functional unitis protected with an alkyl, aryl, or heteroaryl ester or amide group tomake the HPP or HPC more lipophilic.

In certain embodiments, a functional unit of a HPP or HPC comprises amoiety of a retinoid or retinoid-related compound. A retinoid-relatedcompound is a compound comprising a retinoid structure, a retinoidmetabolite, or an agent that can be metabolized into a retinoid orretinoids metabolite after a HPP or HPC penetrates one or morebiological barriers. A retinoid-related compound further includes acompound that is an analog or mimic of a retinoid or a retinoidmetabolite, or an agent that can be metabolized into an analogue ormimic of a retinoid or a retinoid metabolite, after a HPP or HPCpenetrates one or more biological barriers. Examples of retinoidsinclude retinol (vitamin A), retinal, retiferol, tretinoin(all-trans-retinoic acid, e.g. retinoic acid, Retin-A), isotretinoin,alitretinoin (9-cis-retinoic acid), etretinate, acitretin, tazarotene,bexarotene and Adapalene.

In certain embodiments, a transportational unit of a HPP or HPCcomprises a protonatable amine group that is capable of facilitating orenhancing the transportation or crossing of the HPP or HPC through oneor more biological barriers. In certain embodiments, the protonatableamine group is substantially protonated at the pH of the biologicalbarriers through which a HPP or HPC penetrates. In certain embodiments,the amine group can be reversibly protonated or deprotonated.

In certain embodiments, a linker covalently links the functional unit tothe transportational unit of a HPP and comprises a bond that is capableof being cleaved after the HPP penetrates across one or more biologicalbarriers. The cleavable bond comprises, for example, a covalent bond, anether, a thioether, an amide, an ester, a thioester, a carbonate, acarbamate, a phosphate or an oxime bond.

In certain embodiments, a HPP or HPC of a retinoid or retinoid-relatedcompound comprises one or two primary, secondary or tertiary aminegroups that exist in the protonated form at physiological pH. In certainembodiments, the HPP or HPC comprises one primary, secondary or tertiaryamine group that exists in the protonated form at physiological pH.

Another aspect of the invention relates to a pharmaceutical compositioncomprising at least one HPP or HPC of a retinoid or retinoid-relatedcompound and a pharmaceutically acceptable carrier.

Another aspect of the invention relates to a method for penetrating abiological barrier using a HPP or HPC of a retinoid or retinoid-relatedcompound.

Another aspect of the invention relates to a method for diagnosing theonset, development, or remission of a condition in a biological subjectby using a HPP or HPC of a retinoid or retinoid-related compound. Incertain embodiments, the HPP (or HPC) or the functional unit thereof isdetectable. In certain embodiments, the HPP or the functional unit ofthe HPP is inherently detectable, labeled with, or conjugated to, adetectable marker.

Another aspect of the invention relates to a method for screeningfunctional units, linkers, or transportational units for desiredcharacteristics.

Another aspect of the invention relates to a method for preventing,ameliorating, or treating a condition in a biological subject byadministering to the subject a composition in accordance with theinvention. In certain embodiments, the method relates to treating acondition in a subject treatable by retinoids or retinoid-relatedcompounds by administering to the subject a therapeutically effectiveamount of a HPP of a retinoid or retinoid-related compound, or apharmaceutical composition thereof. In certain embodiments, theconditions treatable by the method include, without limitation, VitaminA deficiency conditions (e.g. nyctalopia, keratomalacia, keratinization,dry skin, lowered resistance to infection, decreased growth rate, slowbone development, thickening of bone, diminished production of corticalsteroids, and fetal malformations), infection-related conditions (e.g.herpes simplex infections and lowered resistance to infections), skinconditions (e.g. keratinization, dry skin, skin damage through sunexposure (e.g. photoaging), hyperpigmented macules (liver spot),wrinkles, elastosis and premature aging (e.g. wrinkles), drug-inducedphotosensitivity, diminished production of cortical steroids, epidermalwound healing, keloids, hyperkeratotic skin disease, Darier's disease,lamellar ichthyosis, pityriasis rubra pilaris, lichen planus, refractoryrosacea, keratosis palmaris et plantaris, leukoplakia, xerodermapigmentosum, Kaposi's sarcoma, AIDS-related Kaposi's sarcoma, cutaneousT-cell lymphoma (CTCL), hyperproliferative skin diseases (e.g.psoriasis, basal cell carcinomas), disorders of keratinization andkeratosis, neoplastic diseases, disorders of the sebaceous glands (e.g.acne vulgaris, recalcitrant cystic acne, acne and seborrhoicdermatitis)), eye conditions (e.g. nyctalopia, keratinization,xerophthalmia and Grover's disease), bone conditions (e.g. bonethickening and myelodysplastic syndromes), hair loss, tumor and relatedconditions (e.g. benign tumor, breast cancer, colon-rectum cancer, lungor other respiratory system cancers, skin cancer, basal cell carcinoma,cervical cancer, mycosis fungoides, cutaneous T-cell lymphoma (CTCL),squamous cell skin cancer, second primary tumors, head and neckcarcinoma, ovarian cancer, prostate cancer, and renal cell cancer), andmetabolic disorders (e.g. diabetes such as type 2 diabetes).

In certain embodiments, a pharmaceutical composition of a HPP or HPC isadministrated to a biological subject via various routes including, butnot limited to, oral, enteral, buccal, nasal, topical, rectal, vaginal,aerosol, transmucosal, epidermal, transdermal, dermal, ophthalmic,pulmonary, subcutaneous, and/or parenteral routes. In certain preferredembodiments, a pharmaceutical composition of a HPP or HPC isadministered orally, transdermally, topically, subcutaneously and/orparenterally.

In accordance with the advantages of the invention, without intending tobe limited by any particular mechanism, a therapeutically effectiveamount of a HPP or HPC can be administered locally to a site ofcondition with a less dosage at a higher concentration. The advantagesof the invention also include, for example, avoidance of systematicadministration, reduction of adverse effects (e.g., pain of injection,gastrointestinal/renal effects, and other side effect), and possiblenovel treatments due to high local concentration of a HPP, HPC or activeagent. The advantages further include, for example, systematicadministration of a HPP or HPC to a biological subject to achieve fasterand more efficient bioavailability, penetration of biological barriers(e.g., the blood brain barrier) which have been difficult to cross, andnew indications as a result of passing through biological barriers.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1: Cumulative amounts of 9-cis-retinoic acid 1-piperidineethylester.HBr (5% solution, A), N,N-diethylaminoethyl 13-cis-retinoate.HBr(5% solution, B), N,N-diethylaminoethyl all-trans-retinoate.HBr (5%solution, C), retinyl N,N-dimethyl-2-aminoacetate.HCl (5% solution, D),N,N-diethylaminoethyl4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)ethenyl]benzoate.HCl(5% solution, E), 9-cis-retinoic acid (5% suspention, F),13-cis-retinoic acid (5% suspention, G), all-trans-retinoic acid (5%suspention, H), vitamin A (5% suspention, I), and bexaroten (5%suspention, J), crossing isolated human skin tissue in Franz cells(n=5). In each case, the vehicle was a pH 7.4 phosphate buffer (0.2 M).

DETAILED DESCRIPTION OF THE INVENTION I. Structures of High PenetrationProdrug (HPP) or High Penetration Composition (HPC)

One aspect of the invention is directed to a high penetration prodrug(HPP) or a high penetration composition (HPC). The term “highpenetration prodrug” or “HPP” or “high penetration composition” or “HPC”as used herein refers to a composition comprising a functional unitcovalently linked to a transportational unit through a linker.

A functional unit of a HPP or HPC which comprises a moiety of a parentdrug has the properties of: 1) the delivery of the parent drug or theHPP/HPC into a biological subject and/or the transportation of theparent drug across a biological barrier are/is desired, 2) the HPP/HPCis capable of penetrating or crossing a biological barrier, and 3) theHPP/HPC is capable of being cleaved so as to turn the moiety of a parentdrug into the parent drug or a metabolite of the parent drug.

In certain embodiments, a functional unit may be hydrophilic,lipophilic, or amphiphilic (hydrophilic and lipophilic). The lipophilicmoiety of the functional unit may be inherent or achieved by convertingone or more hydrophilic moieties of the functional unit to lipophilicmoieties. For example, a lipophilic moiety of a functional unit isproduced by converting one or more hydrophilic groups of the functionalunit to lipophilic groups via organic synthesis. Examples of hydrophilicgroups include, without limitation, carboxylic, hydroxyl, thiol, amine,phosphate/phosphonate, guanidine and carbonyl groups. Lipophilicmoieties produced via the modification of these hydrophilic groupsinclude, without limitation, ethers, thioethers, esters, thioesters,carbonates, carbamates, amides, phosphates and oximes. In certainembodiments, a functional unit is lipophilicized by acetylation. Incertain embodiments, a functional unit is lipophilicized byesterification.

In certain embodiments, a parent drug of a HPP or HPC is selected fromthe group consisting of a retinoid and retinoid-related compound. Themoiety of a retinoid or retinoid-related compound can be furtherconverted to a lipophilic moiety as described supra.

Retinoids are well known in the art and are used in connection withvarious conditions. As used herein, a retinoid refers to a compound thatcomprises a four-isoprenoid uint. Examples of retinoids include retinol(vitamin A), retinal, retiferol, tretinoin (all-trans-retinoic acid,e.g. retinoic acid, Retin-A), isotretinoin, alitretinoin (9-cis-retinoicacid), etretinate, acitretin, tazarotene, bexarotene and Adapalene.Moreover, examples of retinoids include, but are not limited tochemicals comprising a structure selected from the group consisting ofStructure R1, Structure R2, Structure R3, Structure R4, Structure R5,Structure R6, Structure R7, Structure R8, Structure R9, Structure R10,Structure R11, Structure R12, Structure R13, Structure R14, StructureR15, Structure R16, Structure R17, Structure R18, Structure R19,Structure R20, Structure R21, Structure R22, Structure R23, StructureR24, Structure R25, Structure R26, Structure R27, Structure R28,Structure R29, Structure R30, Structure R31, Structure R32, StructureR33, Structure R34, Structure R35, Structure R36, Structure R37,Structure R38, and Structure R39:

including stereoisomers and pharmaceutically acceptable salts thereof,wherein:

X₁-X₆ are independently selected from the group consisting of H, OH, Cl,Br, F, I, substituted and unsubstituted alkyl, substituted andunsubstituted perfluoroalkyl, and substituted and unsubstituted alkyloxywherein in certain embodiments, the alkyl, perfluoroalkyl or alkyloxygroup comprises 1-6 carbon atoms;

R₄ is selected from the group consisting of H, OH, Cl, Br, F, I,substituted and unsubstituted alkyl, substituted and unsubstitutedalkyloxy, substituted and unsubstituted perfluoroalkyl, and substitutedand unsubstituted alkyl halide, wherein in certain embodiments, thealkyl, alkyloxy, perfluoroalkyl or alkyl halide group comprises 1-6carbon atoms;

R₅ is selected from the group consisting of H, OH, Cl, Br, F, I,substituted and unsubstituted alkyl, substituted and unsubstitutedalkyloxy, substituted and unsubstituted perfluoroalkyl, and substitutedand unsubstituted alkyl halide, wherein in certain embodiments, thealkyl, alkyloxy, perfluoroalkyl or alkyl halide group comprises 1-6carbon atoms;

R₂₁ and R₂₂ are independently selected from the group consisting of H,OH, Cl, Br, F, I, substituted and unsubstituted alkyl, substituted andunsubstituted alkyloxy, substituted and unsubstituted perfluoroalkyl,and substituted and unsubstituted alkyl halide, wherein in certainembodiments, the alkyl, alkyloxy, perfluoroalkyl or alkyl halide groupcomprises 1-6 carbon atoms;

R₆ and R₆ ^(′) taken together is oxygen (═O) or taken alone are the sameor different and independently selected from the group consisting of H,Cl, Br, F, I, OH, substituted and unsubstituted alkyl, substituted andunsubstituted alkyloxy, and substituted and unsubstituted alkyl halide,wherein in certain embodiments, the alkyl, alkyloxy, or alkyl halidegroup comprises 1-6 carbon atoms;

R₇ and R₇′ taken together is oxygen (═O) or taken alone are the same ordifferent and independently selected from the group consisting of H, Cl,Br, F, I, OH, substituted and unsubstituted alkyl, substituted andunsubstituted alkyloxy, and substituted and unsubstituted alkyl halide,wherein in certain embodiments, the alkyl, alkyloxy, or alkyl halidegroup comprises 1-6 carbon atoms;

R₈ and R₈′ taken together is oxygen (═O) or taken alone are the same ordifferent and independently selected from the group consisting of H, Cl,Br, F, I, OH, substituted and unsubstituted alkyl, substituted andunsubstituted alkyloxy, and substituted and unsubstituted alkyl halide,wherein in certain embodiments, the alkyl, alkyloxy, or alkyl halidegroup comprises 1-6 carbon atoms;

R₉ and R₉′ taken together is oxygen (═O) or taken alone are the same ordifferent and independently selected from the group consisting of H, Cl,Br, F, I, OH, substituted and unsubstituted alkyl, substituted andunsubstituted alkyloxy, and substituted and unsubstituted alkyl halide,wherein in certain embodiments, the alkyl, alkyloxy, or alkyl halidegroup comprises 1-6 carbon atoms;

R₁₀ is selected from the group consisting of H, Cl, Br, F, I, OH,substituted and unsubstituted alkyl, substituted and unsubstitutedalkyloxy, and substituted and unsubstituted alkyl halide, wherein incertain embodiments, the alkyl, alkyloxy, or alkyl halide groupcomprises 1-6 carbon atoms; and

T_(R) is selected from the group consisting of —CH₂═C—, —CH═CH—, —C≡C—,—C(═O)NH—, —C(═S)NH—, —C(═O)O—, —OC(═O)—, —C(═O)S—, —C(═O)CH₂—, and—CH₂C(═O)—.

A retinoid-related compound is a compound comprising a retinoidstructure, a retinoid metabolite, or an agent that can be metabolizedinto a retinoid or retinoids metabolite after a HPP or HPC penetratesone or more biological barriers. A retinoid-related compound furtherincludes a compound that is an analog or mimic of a retinoid or aretinoid metabolite, or an agent that can be metabolized into an analogor mimic of a retinoid or a retinoid metabolite, after a HPP or HPCpenetrates one or more biological barriers.

In certain embodiments, a functional unit of a HPP of a retinoid orretinoid-related compound comprises a moiety having a structure selectedfrom the group consisting of Structure F1, Structure F2, Structure F3,Structure F4, Structure F5, Structure F6, Structure F7, Structure F8,Structure F9, Structure F10, Structure F11, Structure F12, StructureF13, Structure F14, Structure F15, Structure F16, Structure F17,Structure F18, Structure F19, Structure F20, Structure F21, StructureF22, Structure F23, Structure F24, Structure F25, Structure F26,Structure F27, Structure F28, Structure F29, Structure F30, StructureF31, Structure F32, Structure F33, Structure F34, Structure F35,Structure F36, Structure F37, Structure F38, Structure F39, StructureF40 and Structure F41:

including stereoisomers and pharmaceutically acceptable salts thereof,wherein:

R₁ is selected from the group consisting of H, substituted andunsubstituted alkyl, substituted and unsubstituted alkyloxyl,substituted and unsubstituted alkenyl, substituted and unsubstitutedalkynyl, substituted and unsubstituted aryl and substituted andunsubstituted heteroaryl residues;

R₂ is selected from the group consisting of H, substituted andunsubstituted alkyl, substituted and unsubstituted alkyloxyl,substituted and unsubstituted alkenyl, substituted and unsubstitutedalkynyl, substituted and unsubstituted aryl and substituted andunsubstituted heteroaryl residues;

X is selected from the group consisting of O, S, and NH;

X₁-X₈ are independently selected from the group consisting of H, OH, Cl,Br, F, I, substituted and unsubstituted alkyl, substituted andunsubstituted perfluoroalkyl, and substituted and unsubstituted alkyloxywherein in certain embodiments, the alkyl, perfluoroalkyl or alkyloxygroup comprises 1-6 carbon atoms;

R₄ is selected from the group consisting of H, OH, Cl, Br, F, I,substituted and unsubstituted alkyl, substituted and unsubstitutedalkyloxy, substituted and unsubstituted perfluoroalkyl, and substitutedand unsubstituted alkyl halide, wherein in certain embodiments, thealkyl, alkyloxy, perfluoroalkyl or alkyl halide group comprises 1-6carbon atoms;

R₅ is selected from the group consisting of H, OH, Cl, Br, F, I,substituted and unsubstituted alkyl, substituted and unsubstitutedalkyloxy, substituted and unsubstituted perfluoroalkyl, and substitutedand unsubstituted alkyl halide, wherein in certain embodiments, thealkyl, alkyloxy, perfluoroalkyl or alkyl halide group comprises 1-6carbon atoms;

R₂₁ and R₂₂ are independently selected from the group consisting of H,OH, Cl, Br, F, I, substituted and unsubstituted alkyl, substituted andunsubstituted alkyloxy, substituted and unsubstituted perfluoroalkyl,and substituted and unsubstituted alkyl halide, wherein in certainembodiments, the alkyl, alkyloxy, perfluoroalkyl or alkyl halide groupcomprises 1-6 carbon atoms;

R₆ and R₆′ taken together is oxygen (═O) or taken alone are the same ordifferent and independently selected from the group consisting of H, Cl,Br, F, I, OH, substituted and unsubstituted alkyl, substituted andunsubstituted alkyloxy, and substituted and unsubstituted alkyl halide,wherein in certain embodiments, the alkyl, alkyloxy, or alkyl halidegroup comprises 1-6 carbon atoms;

R₇ and R₇′ taken together is oxygen (═O) or taken alone are the same ordifferent and independently selected from the group consisting of H, Cl,Br, F, I, OH, substituted and unsubstituted alkyl, substituted andunsubstituted alkyloxy, and substituted and unsubstituted alkyl halide,wherein in certain embodiments, the alkyl, alkyloxy, or alkyl halidegroup comprises 1-6 carbon atoms;

R₈ and R₈′ taken together is oxygen (═O) or taken alone are the same ordifferent and independently selected from the group consisting of H, Cl,Br, F, I, OH, substituted and unsubstituted alkyl, substituted andunsubstituted alkyloxy, and substituted and unsubstituted alkyl halide,wherein in certain embodiments, the alkyl, alkyloxy, or alkyl halidegroup comprises 1-6 carbon atoms;

R₉ and R₉′ taken together is oxygen (═O) or taken alone are the same ordifferent and independently selected from the group consisting of H, Cl,Br, F, I, OH, substituted and unsubstituted alkyl, substituted andunsubstituted alkyloxy, and substituted and unsubstituted alkyl halide,wherein in certain embodiments, the alkyl, alkyloxy, or alkyl halidegroup comprises 1-6 carbon atoms;

R₁₀ and R₁₀′ taken together is oxygen (═O) or taken alone are the sameor different and independently selected from the group consisting of H,Cl, Br, F, I, OH, substituted and unsubstituted alkyl, substituted andunsubstituted alkyloxy, and substituted and unsubstituted alkyl halide,wherein in certain embodiments, the alkyl, alkyloxy, or alkyl halidegroup comprises 1-6 carbon atoms;

T_(R) is selected from the group consisting of —CH₂═C—, —CH═CH—, —C≡C—,—C(═O)NH—, —C(═S)NH—, —C(═O)O—, —OC(═O)—, —C(═O)S—, —C(═O)CH₂—, and—CH₂C(═O)—;

as used herein, unless specified otherwise, the term “HA” is nothing ora pharmaceutically acceptable acid, e.g. hydrochloride, hydrobromide,hydroiodide, nitric acid, sulfic acid, bisulfic acid, phosphoric acid,phosphorous acid, phosphonic acid, isonicotinic acid, acetic acid,lactic acid, salicylic acid, citric acid, tartaric acid, pantothenicacid, bitartaric acid, ascorbic acid, succinic acid, maleic acid,gentisinic acid, fumaric acid, gluconic acid, glucaronic acid, saccharicacid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid,ethanesulfonic acid, benzensulfonic acid, p-toluenesulfonic acid orpamoic acid; and

any CH₂ groups may be replaced with 0, S, or NH.

As used herein, the term “pharmaceutically acceptable salt” means thosesalts of compounds of the invention that are safe for application in asubject. Pharmaceutically acceptable salts include salts of acidic orbasic groups present in compounds of the invention. Pharmaceuticallyacceptable acid addition salts include, but are not limited to,hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate,phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate,citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate,maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate,formate, benzoate, glutamate, methanesulfonate, ethanesulfonate,benzensulfonate, p-toluenesulfonate and pamoate (i.e.,1,11-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Certain compounds ofthe invention can form pharmaceutically acceptable salts with variousamino acids. Suitable base salts include, but are not limited to,aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, anddiethanolamine salts. For a review on pharmaceutically acceptable saltssee BERGE ET AL., 66 J. PHARM. SCI. 1-19 (1 977), incorporated herein byreference.

As used herein, the term “pharmaceutically acceptable acid” means acidsthat can form salts with compounds of the invention that are safe forapplication in a subject. Examples of pharmaceutically acceptable acidinclude, but are not limited to, e.g. hydrochloride, hydrobromide,hydroiodide, nitric acid, sulfic acid, bisulfic acid, phosphoric acid,phosphorous acid, phosphonic acid, isonicotinic acid, acetic acid,lactic acid, salicylic acid, citric acid, tartaric acid, pantothenicacid, bitartaric acid, ascorbic acid, succinic acid, maleic acid,gentisinic acid, fumaric acid, gluconic acid, glucaronic acid, saccharicacid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid,ethanesulfonic acid, benzensulfonic acid, p-toluenesulfonic acid andpamoic acid.

As used herein, unless specified otherwise, the term “alkyl” means abranched or unbranched, saturated or unsaturated, monovalent ormultivalent hydrocarbon group, including saturated alkyl groups, alkenylgroups and alkynyl groups. Examples of alkyl include, but are notlimited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl,pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, ethenyl,propenyl, butenyl, isobutenyl, pentenyl, hexenyl, heptenyl, octenyl,nonenyl, decenyl, undecenyl, dodecenyl, ethynyl, propynyl, butynyl,isobutynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl,undecynyl, dodecynyl, methylene, ethylene, propylene, isopropylene,butylene, isobutylene, t-butylene, pentylene, hexylene, heptylene,octylene, nonylene, decylene, undecylene and dodecylene. In certainembodiments, the hydrocarbon group contains 1 to 30 carbons. In certainembodiments, the hydrocarbon group contains 1 to 20 carbons. In certainembodiments, the hydrocarbon group contains 1 to 12 carbons. In certainembodiments, the hydrocarbon group contains 1 to 6 carbons.

As used herein, unless specified otherwise, the term “cycloalkyl” meansan alkyl which contains at least one ring and no aromatic rings.Examples of cycloalkyl include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl. In certainembodiments, the hydrocarbon chain contains 1 to 30 carbons. In certainembodiments, the hydrocarbon group contains 1 to 20 carbons. In certainembodiments, the hydrocarbon group contains 1 to 12 carbons. In certainembodiments, the hydrocarbon group contains 1 to 6 carbons.

As used herein, unless specified otherwise, the term “heterocycloalkyl”means a cycloalkyl wherein at least one ring atom is a non-carbon atom.Examples of the non-carbon ring atom include, but are not limited to, S,O and N.

As used herein, unless specified otherwise, the term “alkoxyl” means analkyl, cycloalkyl or heterocycloalkyl, which contains one or more oxygenatoms. Examples of alkoxyl include, but are not limited to, —CH₂—OH,—OCH₃, —O-alkyl, -alkyl-OH, -alkyl-O-alkyl-, wherein the two alkyls canbe the same or different.

As used herein, unless specified otherwise, the term “alkyl halide”means an alkyl, cycloalkyl or heterocycloalkyl, which contains one ormore halogen atoms, wherein the halogen atoms can be the same ordifferent. The term “halogen” means fluorine, chlorine, bromine oriodine. Examples of alkyl halide include, but are not limited to,-alkyl-F, -alkyl-Cl, -alkyl-Br, -alkyl-I, -alkyl(F)—, -alkyl(Cl)—,-alkyl(Br)— and -alkyl(I)—.

As used herein, unless specified otherwise, the term “alkylthio” meansan alkyl, cycloalkyl or heterocycloalkyl, which contains one or moresulfur atoms. Examples of alkylthio include, but are not limited to,—CH₂—SH, —SCH₃, —S-alkyl, -alkyl-SH, -alkyl-S-alkyl-, wherein the twoalkyls can be the same or different.

As used herein, unless specified otherwise, the term “alkylamino” meansan alkyl, cycloalkyl or heterocycloalkyl, which contains one or morenitrogen atoms. Examples of alkylamino include, but are not limited to,—CH₂—NH, —NCH₃, —N(alkyl)-alkyl, —N-alkyl, -alkyl-NH₂, -alkyl-N-alkyland -alkyl-N(alkyl)-alkyl wherein the alkyls can be the same ordifferent.

As used herein, unless specified otherwise, the term “alkylcarbonyl”means an alkyl, cycloalkyl or heterocycloalkyl, which contains one ormore carbonyl groups. Examples of alkylcarbonyl group include, but arenot limited to, aldehyde group (—R—C(O)—H), ketone group (—R—C(O)—R′),carboxylic acid group (R—COOH), ester group (—R—COO—R′), carboxamide,(—R—COO—N(R′)R″), enone group (—R—C(O)—C(R′)═C(R″)R′″), acyl halidegroup (—R—C(O)—X) and acid anhydride group (—R—C(O)—O—C(O)—R′), whereinR, R′, R″ and R′″ are the same or different alkyl, cycloalkyl, orheterocycloalkyl.

As used herein, unless specified otherwise, the term “perfluoroalkyl”means an alkyl, cycloalkyl or heterocycloalkyl, which contains one ormore fluoro group, including, without limitation, perfluoromethyl,perfluoroethyl, perfluoropropyl.

As used herein, unless specified otherwise, the term “aryl” means achemical structure comprising one or more aromatic rings. In certainembodiments, the ring atoms are all carbon. In certain embodiments, oneor more ring atoms are non-carbon, e.g. oxygen, nitrogen, or sulfur(“heteroaryl”). Examples of aryl include, without limitation, phenyl,benzyl, naphthalenyl, anthracenyl, pyridyl, quinoyl, isoquinoyl,pyrazinyl, quinoxalinyl, acridinyl, pyrimidinyl, quinazolinyl,pyridazinyl, cinnolinyl, imidazolyl, benzimidazolyl, purinyl, indolyl,furanyl, benzofuranyl, isobenzofuranyl, pyrrolyl, indolyl, isoindolyl,thiophenyl, benzothiophenyl, pyrazolyl, indazolyl, oxazolyl,benzoxazolyl, isoxazolyl, benzisoxazolyl, thiaxolyl, quanidino andbenzothiazolyl.

In certain embodiments, a transportational unit of a HPP comprises aprotonatable amine group that is capable of facilitating thetransportation or crossing of the HPP through one or more biologicalbarriers (e.g., >about 20 times, >about 50 times, >about 100times, >about 300 times, >about 500 times faster than the parent drug).In certain embodiments, the protonatable amine group is substantiallyprotonated at a physiological pH. In certain embodiments, the aminegroup can be reversibly protonated. In certain embodiments, thetransportational unit may or may not be cleaved from the functional unitafter the penetration of HPP through one or more biological barriers. Incertain embodiments, the transportational unit may be from thefunctional unit, especially for retinoids that have at least a freeamino group.

In certain embodiments, the protonatable amine group is selected fromthe group consisting of pharmaceutically acceptable substituted andunsubstituted primary amine groups, pharmaceutically acceptablesubstituted and unsubstituted secondary amine groups, andpharmaceutically acceptable substituted and unsubstituted tertiary aminegroups.

In certain embodiments, the protonatable amine group is selected fromthe group consisting of Structure Na, Structure Nb, Structure Nc,Structure Nd, Structure Ne, Structure Nf, Structure Ng, Structure Nh,Structure Ni, Structure Nj, Structure Nk, Structure Nl, Structure Nm,Structure Nn, Structure No, Structure Np, Structure Nq and Structure Nr:

including stereoisomers and pharmaceutically acceptable salts thereof.

As used herein, unless specified otherwise, each R₁₁—R₁₆ isindependently selected from the group consisting of nothing, H,CH₂COOR₁₁, substituted and unsubstituted alkyl, substituted andunsubstituted cycloalkyl, substituted and unsubstitutedheterocycloalkyl, substituted and unsubstituted aryl, substituted andunsubstituted heteroaryl, substituted and unsubstituted alkoxyl,substituted and unsubstituted alkylthio, substituted and unsubstitutedalkylamino, substituted and unsubstituted perfluoroalkyl, andsubstituted and unsubstituted alkyl halide, wherein any carbon orhydrogen may be further independently replaced with O, S, P, NR₁₁, orany other pharmaceutically acceptable groups.

In certain embodiments, a linker covalently linking a functional unitand a transportational unit of a HPP comprises a bond that is capable ofbeing cleaved after the HPP penetrates across one or more BBs. Thecleavable bond comprises, for example, a covalent bond, an ether,thioether, amide, ester, thioester, carbonate, carbamate, phosphate oroxime bond.

In certain embodiments, a HPP of a retinoid and retinoid-relatedcompound has the following Structure L-1:

including stereoisomers and pharmaceutically acceptable salts thereof,wherein:

F is a functional unit of a HPP of a retinoid or retinoid-relatedcompound. Examples of F include Structure F-1 to Structure F-41 asdefined supra;

T is a transportational unit of a HPP of a retinoid or retinoid-relatedcompound. For example, T is selected from the group consisting ofStructure Na, Structure Nb, Structure Nc, Structure Nd, Structure Ne,Structure Nf, Structure Ng, Structure Nh, Structure Ni, Structure Nj,Structure Nk, Structure Nl, Structure Nm, Structure Nn, Structure No,Structure Np, Structure Nq and Structure Nr as defined supra;

L₁ is selected from the group consisting of nothing, O, S, —N(L₃)-,—N(L₃)-CH₂—O, —N(L₃)—CH₂—N(L₅)-, —O—CH₂—O—, —O—CH(L₃)-O, and—S—CH(L₃)-O—;

L₂ is selected from the group consisting of nothing, O, S, —N(L₃)-,—N(L₃)-CH₂—O, —N(L₃)—CH₂—N(L₅)-, —O—CH₂—O—, —O—CH(L₃)-O, —S—CH(L₃)-O—,—O-L₃-, —N-L₃-, —S-L₃-, —N(L₃)-L₅- and L₃;

L₄ is selected from the group consisting of nothing,

for each L₁, L₂, and L₄, each L₃ and L₅ is independently selected fromthe group consisting of nothing, H, CH₂COOL₆, substituted andunsubstituted alkyl, substituted and unsubstituted cycloalkyl,substituted and unsubstituted heterocycloalkyl, substituted andunsubstituted aryl, substituted and unsubstituted heteroaryl,substituted and unsubstituted alkoxyl, substituted and unsubstitutedalkylthio, substituted and unsubstituted alkylamino, substituted andunsubstituted perfluoroalkyl, and substituted and unsubstituted alkylhalide, wherein any carbon or hydrogen may be further independentlyreplaced with O, S, P, NL₃, or any other pharmaceutically acceptablegroups;

L₆ is independently selected from the group consisting of H, OH, Cl, F,Br, I, substituted and unsubstituted alkyl, substituted andunsubstituted cycloalkyl, and substituted and unsubstitutedheterocycloalkyl, substituted and unsubstituted aryl, substituted andunsubstituted heteroaryl, substituted and unsubstituted alkoxyl,substituted and unsubstituted alkylthio, substituted and unsubstitutedalkylamino, substituted and unsubstituted perfluoroalkyl, andsubstituted and unsubstituted alkyl halide, wherein any carbon orhydrogen may be further independently replaced with O, S, N, P(O)OL₇,CH═CH, C≡C, CHL₇, CL₅L₇, aryl, heteroaryl, or cyclic groups; and

L₇ is independently selected from the group consisting of H, OH, Cl, F,Br, I, substituted and unsubstituted alkyl, substituted andunsubstituted cycloalkyl, and substituted and unsubstitutedheterocycloalkyl, substituted and unsubstituted aryl, substituted andunsubstituted heteroaryl, substituted and unsubstituted alkoxyl,substituted and unsubstituted alkylthio, substituted and unsubstitutedalkylamino, substituted and unsubstituted perfluoroalkyl, andsubstituted and unsubstituted alkyl halide, wherein any carbon orhydrogen may be further independently replaced with O, S, N, P(O)OL₆,CH═CH, C≡C, CHL₆, CL₆L₅, aryl, heteroaryl, or cyclic groups.

In certain embodiments, a HPP or HPC of a retinoid or retinoid-relatedcompound comprises the structure of Structure L-1, includingstereoisomers and pharmaceutically acceptable salts thereof, wherein:

-   -   F, L₁, L₂, and T are defined as supra; and L₄ is —C(═O)—.

Examples of HPPs of Retinoids and Retinoid-Related Compounds.

In certain embodiments, a HPP of a retinoid or retinoid-related compoundincludes a compound having a structure selected from the groupconsisting of Structure 1, Structure 2, Structure 3, Structure 4,Structure 5, Structure 6, Structure 7, Structure 8, Structure 9,Structure 10, Structure 11, Structure 12, Structure 13, Structure 14,Structure 15, Structure 16, Structure 17, Structure 18, Structure 19,Structure 20, Structure 21, Structure 22, Structure 23, Structure 24,Structure 25, Structure 26, Structure 27, Structure 28, Structure 29,Structure 30, Structure 31, Structure 32, Structure 33, Structure 34,Structure 35, Structure 36, Structure 37, Structure 38, and Structure39:

including stereoisomers and pharmaceutically acceptable salts thereof,wherein:

R is selected from the group consisting of nothing, substituted andunsubstituted alkyl, substituted and unsubstituted alkoxyl, substitutedand unsubstituted perfluoroalkyl, substituted and unsubstituted alkylhalide, substituted and unsubstituted alkenyl, substituted andunsubstituted alkynyl, substituted and unsubstituted aryl, andsubstituted and unsubstituted heteroaryl;

R₁, R₂, R₄, R₅, R₆, R₆′, R₇, R₇′, R₈, R₈′, R₉, R₉′, R₁₀, R₁₀′, R₂₁, R₂₂,X, X₁, X₂, X₃, X₄, X₅, X₆, T_(R) and HA are defined the same as supra.

II. Pharmaceutical Compositions Comprising HPPs

Another aspect of the invention relates to a pharmaceutical compositioncomprising at least one HPP of a retinoid or retinoid-related compoundand a pharmaceutically acceptable carrier.

The term “pharmaceutically acceptable carrier” as used herein means apharmaceutically-acceptable material, composition or vehicle, such as aliquid or solid filler, diluent, excipient, solvent or encapsulatingmaterial, involved in carrying or transporting a HPP from one location,body fluid, tissue, organ (interior or exterior), or portion of thebody, to another location, body fluid, tissue, organ, or portion of thebody.

Each carrier is “pharmaceutically acceptable” in the sense of beingcompatible with the other ingredients, e.g., a HPP, of the formulationand suitable for use in contact with the tissue or organ of a biologicalsystem without excessive toxicity, irritation, allergic response,immunogenicity, or other problems or complications, commensurate with areasonable benefit/risk ratio.

Some examples of materials which can serve aspharmaceutically-acceptable carriers include: (1) sugars, such aslactose, glucose and sucrose; (2) starches, such as corn starch andpotato starch; (3) cellulose, and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4)powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients,such as cocoa butter and suppository waxes; (9) oils, such as peanutoil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; (10) glycols, such as propylene glycol; (11) polyols, suchas glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters,such as ethyl oleate and ethyl laurate; (13) agar; (14) bufferingagents, such as magnesium hydroxide and aluminum hydroxide; (15) alginicacid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer'ssolution; (19) alcohol, such as ethyl alcohol and propane alcohol; (20)phosphate buffer solutions; and (21) other non-toxic compatiblesubstances employed in pharmaceutical formulations such as acetone.

The pharmaceutical compositions may contain pharmaceutically acceptableauxiliary substances as required to approximate physiological conditionssuch as pH adjusting and buffering agents, toxicity adjusting agents andthe like, for example, sodium acetate, sodium chloride, potassiumchloride, calcium chloride, sodium lactate and the like.

In one embodiment, the pharmaceutically acceptable carrier is an aqueouscarrier, e.g. buffered saline and the like. In certain embodiments, thepharmaceutically acceptable carrier is a polar solvent, e.g. acetone andalcohol.

The concentration of HPP in these formulations can vary widely, and willbe selected primarily based on fluid volumes, viscosities, body weightand the like in accordance with the particular mode of administrationselected and the biological system's needs. For example, theconcentration can be 0.0001% to 100%, 0.001% to 50%, 0.01% to 30%, 0.1%to 10% wt.

The compositions of the invention can be administered for prophylactic,therapeutic, and/or hygienic use. Such administration can be topical,mucosal, e.g., oral, nasal, vaginal, rectal, parenteral, transdermal,subcutaneous, intramuscular, intravenous, via inhalation, ophthalmic andother convenient routes. The pharmaceutical compositions can beadministered in a variety of unit dosage forms depending upon the methodof administration. For example, unit dosage forms suitable for oraladministration include powder, tablets, pills, capsules and lozenges.

Thus, a typical pharmaceutical composition for intravenousadministration would be about 10⁻¹⁹ g to about 100 g, about 10⁻¹⁹ g toabout 10⁻³ g, about 10⁻⁹ g to about 10⁻⁶ g, about 10⁻⁶ g to about 100 g,about 0.001 g to about 100 g, about 0.01 g to about 10 g, or about 0.01g to about 1 g per subject per day. Dosages from about 0.01 mg, up toabout 5 g, per subject per day may be used. Actual methods for preparingparenterally administrable compositions will be known or apparent tothose skilled in the art and are described in more detail in suchpublications as Remington's Pharmaceutical Science, 15th ed., MackPublishing Company, Easton, Pa. (1980).

III. Applications of HPPs i) Methods for Penetrating a BiologicalBarrier.

Another aspect of the invention relates to a method of using acomposition of the invention in penetrating one or more biologicalbarriers in a biological subject. The method comprises a step ofadministering to a biological subject a HPP or a retinoid orretinoid-related compound, or a pharmaceutical composition thereof. Incertain embodiments, a HPP exhibits more than about 20 times or higher,50 times or higher, >about 100 times or higher, >about 200 timehigher, >about 300 times or higher, >about 500 times or higher, >about1,000 times or higher penetration rate through one or more biologicalbarriers than its parent drug.

The term “biological barrier” as used herein refers to a biologicallayer that separates an environment into different spatial areas orcompartments, which separation is capable of modulating (e.g.restricting, limiting, enhancing or taking no action in) the passingthrough, penetrating or translocation of substance or matter from onecompartment/area to another. The different spatial areas or compartmentsas referred to herein may have the same or different chemical orbiological environment(s). The biological layer as referred hereinincludes, but is not limited to, a biological membrane, a cell layer, abiological structure, an inner surface of subjects, organisms, organs orbody cavities, an external surface of subjects, organisms, organs orbody cavities, or any combination or plurality thereof.

Examples of a biological membrane include a lipid bilayer structure,eukaryotic cell membrane, prokaryotic cell membrane, and intracellularmembrane (e.g., nucleus or organelle membrane, such as membrane orenvelope of Golgi apparatus, rough and smooth endoplasmic reticulum(ER), ribosomes, vacuoles, vesicles, liposomes, mitochondria, lysosome,nucleus, chloroplasts, plastids, peroxisomes or microbodies).

The lipid bilayer referred to herein is a double layer of lipid-classmolecules, including, but not limited to, phospholipids and cholesterol.In a particular embodiment, lipids for bilayer are amphiphilic moleculesconsisting of polar head groups and non-polar fatty acid tails. Thebilayer is composed of two layers of lipids arranged so that theirhydrocarbon tails face one another to form an oily core held together bythe hydrophobic effect, while their charged heads face the aqueoussolutions on either side of the membrane. In another particularembodiment, the lipid bilayer may contain one or more embedded proteinand/or sugar molecule(s).

Examples of a cell layer include a lining of eukaryotic cells (e.g.,epithelium, lamina propria and smooth muscle or muscularis mucosa (ingastrointestinal tract)), a lining of prokaryotic cells (e.g., surfacelayer or S-layer which refers to a two dimensional structuremonomolecular layer composed of identical proteins or glycoproteins,specifically, an S-layer refers to a part of a cell envelope commonlyfound in bacteria and archaea), a biofilm (a structured community ofmicroorganisms encapsulated within a self-developed polymeric matrix andadherent to a living or inert surface), and a plant cell layer (e.g.,empidermis). The cells may be normal cells or pathological cells (e.g.disease cells, cancer cells).

Examples of biological structures include structures sealed by tight oroccluding junctions which provide a barrier to the entry of toxins,bacteria and viruses, e.g. the blood milk barrier and the blood brainbarrier (BBB). In particular, BBB is composed of an impermeable class ofendothelium, which presents both a physical barrier through tightjunctions adjoining neighboring endothelial cells and a transportbarrier comprised of efflux transporters. The biological structure mayalso include a mixture of cells, proteins and sugars (e.g. blood clots).

Examples of the inner surface of subjects, organisms, organs or bodycavities include buccal mucosa, esophageal mucosa, gastric mucosa,intestinal mucosa, olfactory mucosa, oral mucosa, bronchial mucosa,uterine mucosa and endometrium (the mucosa of the uterus, inner layer ofthe wall of a pollen grain or the inner wall layer of a spore), or acombination or plurality thereof.

Examples of the external surface of subjects, organisms, organs or bodycavities include capillaries (e.g. capillaries in the heart tissue),mucous membranes that are continuous with skin (e.g. such as at thenostrils, the lips, the ears, the genital area, and the anus), outersurface of an organ (e.g. liver, lung, stomach, brain, kidney, heart,ear, eye, nose, mouth, tongue, colon, pancreas, gallbladder, duodenum,rectum stomach, colonrectum, intestine, vein, respiratory system,vascular, the anorectum and pruritus ani), skin, cuticle (e.g. deadlayers of epidermal cells or keratinocytes or superficial layer ofoverlapping cells covering the hair shaft of an animal, a multi-layeredstructure outside the epidermis of many invertebrates, plant cuticles orpolymers cutin and/or cutan), external layer of the wall of a pollengrain or the external wall layer of a spore), and a combination orplurality thereof.

In addition, a biological barrier further includes a sugar layer, aprotein layer or any other biological layer, or a combination orplurality thereof. For example, skin is a biological barrier that has aplurality of biological layers. A skin comprises an epidermis layer(outer surface), a demis layer and a subcutaneous layer. The epidermislayer contains several layers including a basal cell layer, a spinouscell layer, a granular cell layer, and a stratum corneum. The cells inthe epidermis are called keratinocytes. The stratum corneum (“hornylayer”) is the outmost layer of the epidermis, wherein cells here areflat and scale-like (“squamous”) in shape. These cells contain a lot ofkeratin and are arranged in overlapping layers that impart a tough andoilproof and waterproof character to the skin's surface.

ii) Methods for Diagnosing a Condition in a Biological System.

Another aspect of the invention relates to a method of using acomposition of the invention in diagnosing a condition in a biologicalsystem. The method comprises the following steps:

1) administering a composition comprising a HPP of a retinoid orretinoid-related compound to the biological subject;

2) detecting the presence, location or amount of the HPP, the functionalunit of the HPP or a metabolite thereof in the biological subject; and

3) determining a condition in the biological system.

In certain embodiments, the HPP (or the agent cleaved from the HPP)aggregates in the site of action where a condition occurs. In certainembodiments, the presence, location or amount of the functional unit ofthe HPP is also detected. In certain embodiments, the onset,development, progress, or remission of a condition (e.g., tumor)associated is also determined.

In certain embodiments, the HPP is labeled with or conjugated to adetectable agent. Alternatively, the HPP is prepared to includeradioisotopes for detection. Numerous detectable agents are availablewhich can be generally grouped into the following categories:

(a) Radioisotopes, such as ³⁵S, 14C, ¹³C, ¹⁵N, ¹²⁵I, ³H, and ¹³¹I. Thediagnostic agent can be labeled with the radioisotope using thetechniques known in the art and radioactivity can be measured usingscintillation counting; in addition, the diagnostic agent can be spinlabeled for electron paramagnetic resonance for carbon and nitrogenlabeling.

(b) Fluorescent agents such as BODIPY, BODIPY analogs, rare earthchelates (europium chelates), fluorescein and its derivatives, FITC, 5,6carboxyfluorescein, rhodamine and its derivatives, dansyl, Lissamine,phycoerythrin, green fluorescent protein, yellow fluorescent protein,red fluorescent protein and Texas Red. Fluorescence can be quantifiedusing a fluorometer.

(c) Various enzyme-substrate agents, such luciferases (e.g., fireflyluciferase and bacterial luciferase), luciferin,2,3-dihydrophthalazinediones, malate dehydrogenase, urease, peroxidasesuch as horseradish peroxidase (HRPO), alkaline phosphatase,β-galactosidase, glucoamylase, lysozyme, saccharide oxidases (e.g.,glucose oxidase, galactose oxidase, and glucose-6-phosphatedehydrogenase), heterocyclic oxidases (such as uricase and xanthineoxidase), lactoperoxidase, microperoxidase, and the like. Examples ofenzyme-substrate combinations include, for example: (i) Horseradishperoxidase (HRPO) with hydrogen peroxidase as a substrate, wherein thehydrogen peroxidase oxidizes a dye precursor (e.g., orthophenylenediamine (OPD) or 3,3′,5,5′-tetramethyl benzidine hydrochloride (TMB));(ii) alkaline phosphatase (AP) with para-Nitrophenyl phosphate aschromogenic substrate; and (iii) β-D-galactosidase (β-D-Gal) with achromogenic substrate (e.g., p-nitrophenyl-β-D-galactosidase) orfluorogenic substrate 4-methylumbelliferyl-β-D-galactosidase.

In certain embodiments, the detectable agent is not necessarilyconjugated to the diagnostic agent but is capable of recognizing thepresence of the diagnostic agent and the diagnostic agent can bedetected.

In certain embodiments, the HPP of the invention can be provided in akit, i.e., a packaged combination of reagents in predetermined amountswith instructions for performing the diagnostic assay. Where the HPP islabeled with an enzyme, the kit will include substrates and cofactorsrequired by the enzyme (e.g., a substrate precursor which provides thedetectable chromophore or fluorophore). In addition, other additives maybe included such as stabilizers, buffers (e.g., a block buffer or lysisbuffer) and the like. The relative amounts of the various reagents maybe varied widely to provide for concentrations in solution of thereagents which substantially optimize the sensitivity of the assay.Particularly, the reagents may be provided as dry powders, usuallylyophilized, including excipients which on dissolution will provide areagent solution having the appropriate concentration.

iii) Methods for Screening a Substance for a Desired Character

Another aspect of the invention relates to a method of screening a HPPfor a desired character.

In certain embodiments, the method comprises:

1) covalently linking a test functional unit to a transportational unitthrough a linker to form a test composition (or covalently linking afunctional unit to a test transportational unit through a linker, orcovalently linking a functional unit to a transportational unit througha test linker)2) administering the test composition to a biological system; and3) determining whether the test composition has the desired nature orcharacter.

In one embodiment, a desired character may include, for example, 1) theability of a test functional unit to form a high penetration compositionor convert back to a parent drug, 2) the penetration ability and/or rateof a test composition, 3) the efficiency and/or efficacy of a testcomposition, 4) the transportational ability of a test transportationalunit, and 5) the cleavability of a test linker.

iv) Methods for Treating a Condition in a Biological Subject

Another aspect of the invention relates to a method of using acomposition of the invention in treating a condition in a biologicalsystem. The method comprises administering the pharmaceuticalcomposition to the biological system.

The term “treating” as used herein means curing, alleviating,inhibiting, or preventing. The term “treat” as used herein means cure,alleviate, inhibit, or prevent. The term “treatment” as used hereinmeans cure, alleviation, inhibition or prevention.

The term “biological system,” “biological subject” or “subject” as usedherein means an organ, a group of organs that work together to perform acertain task, an organism, or a group of organisms. The term “organism”as used herein means an assembly of molecules that function as a more orless stable whole and has the properties of life, such as animal, plant,fungus, or micro-organism.

The term “animal” as used herein means an eukaryotic organismcharacterized by voluntary movement. Examples of animal include, withoutlimitation, vertebrata (e.g. human, mammals, birds, reptiles,amphibians, fishes, marsipobranchiata and leptocardia), tunicata (e.g.thaliacea, appendicularia, sorberacea and ascidioidea), articulata (e.g.insecta, myriapoda, malacapoda, arachnida, pycnogonida, merostomata,crustacea and annelida), gehyrea (anarthropoda), and helminthes (e.g.rotifera).

The term “plant” as used herein means organisms belonging to the kindomPlantae. Examples of plant include, without limitation, seed plants,bryophytes, ferns and fern allies. Examples of seed plants include,without limitation, cycads, ginkgo, conifers, gnetophytes, angiosperms.Examples of bryophytes include, without limitation, liverworts,hornworts and mosses. Examples of ferns include, without limitation,ophioglossales (e.g. adders-tongues, moonworts, and grape-ferns),marattiaceae and leptosporangiate ferns. Examples of fern alliesinclude, without limitation, lycopsida (e.g. clubmosses, spikemosses andquillworts), psilotaceae (e.g. lycopodiophyta and whisk ferns) andequisetaceae (e.g. horsetails).

The term “fungus” as used herein means a eukaryotic organism that is amember of the kingdom Fungi. Examples of fungus include, withoutlimitation, chytrids, blastocladiomycota, neocallimastigomycota,zygomycota, glomeromycota, ascomycota and basidiomycota.

The term “micro-organism” as used herein means an organism that ismicroscopic (e.g. with length scale of micrometer). Examples ofmicro-organism include, without limitation, bacteria, fungi, archaea,protists and microscopic plants (e.g. green algae) and microscopicanimals (e.g. plankton, planarian and amoeba).

Some examples of the conditions the method can treat include conditionsthat can be treated by the parent drug of the HPP.

v). Methods of Using HPPs of Retinoids and Retinoid-Related Compoundsand Pharmaceutical Compositions Thereof in Treatments.

Another aspect of the invention relates to a method of using HPPs ofretinoids or retinoid-related compounds, or pharmaceutical compositionsthereof in treating a condition in a biological system or subject byadministering a HPP of a retinoid or retinoid-related compound, or apharmaceutical composition thereof to the biological system or subject.

Retinoids and retinoid-related compounds can be used to regulate a widerange of biological processes in a biological system. Conditions thatare related to such biological processes are treatable by thecorresponding retinoids or retinoid-related compounds, and thereforetreatable by HPPs/HPCs of the retinoids/retinoid-related compounds, anda pharmaceutical composition thereof.

Without being bounded by any theory, it is believed that Vitamin A(retinol) and retinal are in chemical equilibrium in the body andequivalent antixerophthalmic acitivity. Examples of conditions that arerelated to Vitamin A deficiency include, without limitation, nyctalopia,keratomalacia, keratinization, dry skin, lowered resistance toinfection, decreased growth rate, slow bone development, thickening ofbone, diminished production of cortical steroids, and fetalmalformations.

Without being bounded by any theory, it is believed that tretinoin(all-trans-retinoic acid) decreases cohesiveness of follicularepithelial cells with decreased microcomedo formation and stimulatesmitotic activity increased turnover of follicular epithelial cellscausing extrusion of the comedones. Tretinoin has been used in thetreatment of acne vulgaris, photoaging, hyperpigmented macules (liverspot) and premature wrinkles, drug-induced photosensitivity, psoriasis,epidermal wound healing, xerophthalmia, keloids, hyperkeratotic skindisease.

Without being bounded by any theory, it is believed that isotretinoininhibits sebaceous gland function and keratinization. Isotretinoin isindicated for the treatment of severe recalcitrant cystic acne, basalcell carcinoma, cervical cancer, mycosis fungoides (cutaneous T-celllymphoma), Darier's disease, lamellar ichthyosis, pityriasis rubrapilaris, herpes simplex infections, Grover's disease, lichen planus,refractory rosacea, keratosis palmaris et plantaris, leukoplakia,squamous cell skin cancer, and xeroderma pigmentosum.

Without being bounded by any theory, it is believed that alitretinoin(9-cis-retinoic acid) is a naturally-occurring endogenous retinoid thatbinds to and activates all known intracellular retinoid receptorsubtypes (RAR, RAR, RAR, RXR, RXR, and RXR). Once activated thesereceptors function as transcription factors that regulate the expressionof genes that control the process of cellular differentiation andproliferation in both normal and neoplastic cells. Alitretinoin inhibitsthe growth of Kaposi's sarcoma (KS) cells in vitro. Alitretinoin is usedfor the treatment of Kaposi's sarcoma and myelodysplastic syndromes.

Targretin oral formulation is used for the treatment of cutaneous T-celllymphoma (CTCL), head and neck carcinoma, systemic Kaposi's sarcoma,lung cancer, ovarian cancer, prostate cancer, and renal cell cancer.

Retiferol derivatives are used for the treatment of hyperproliferativeskin diseases such as psoriasis, basal cell carcinomas, disorders ofkeratinization and keratosis, neoplastic diseases, disorders of thesebaceous glands such as acne and seborrhoic dermatitis, the conditionsassociated with photodamage, the skin damaged through sun exposure, theeffects of wrinkling, elastosis and premature ageing (Hilpert, et al.,U.S. Pat. No. 6,437,142).

Adapalene is used for the topical treatment of acne vulgaris.

Acyclic retiniods are used for prevention of second primary tumors(Yasutoshi Muto, et al., the New England Journal of Medicine, 340, 1046(1999)).

(E,E,E)-7-(2-n-propoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-3-yl)-6-fluoro-3-methylocta-2,4,6-trienoicacid may be used for the treatment of type 2 diabetes and othermetabolic disorders (Deng T, et al., Biol. Pharm. Bull. 28(7), 1192,2005).

Various retinoids and retinoid-related compounds have been synthesizedand show retinoid activieis. (U.S. Pat. Nos. 5,648,563; 5,648,385;5,618,839; 5,559,248; 5,616,712; 5,616,597; 5,602,135; 5,599,819;5,556,996; 5,534,516; 5,516,904; 5,498,755; 5,470,999; 5,468,879;5,455,265; 5,451,605; 5,426,118; 5,407,937; 5,399,586; 5,399,561;5,391,753). Numerous experimental retinoids compounds, for exemple,4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)ethenyl]benzoicacid (bexaroten, Targretin®), are used for the treatment of cancers andother diseases.

Conditions that are treatable by retinoids or retinoid-related compoundsinclude, but are not limited to, Vitamin A deficiency conditions,infection-related conditions, skin conditions, eye conditions, boneconditions, tumor and related conditions, hair loss, and metabolicdisorders (e.g. diabetes such as type 2 diabetes).

Vitamin A deficiency related conditions include, for example,nyctalopia, keratomalacia, keratinization, dry skin, lowered resistanceto infection, decreased growth rate, slow bone development, thickeningof bone, diminished production of cortical steroids, and fetalmalformations.

Examples of skin conditions include, without limitation, keratinization,dry skin, skin damage through sun exposure (e.g. photoaging),hyperpigmented macules (liver spot), wrinkles, elastosis and prematureaging (e.g. wrinkles), drug-induced photosensitivity, diminishedproduction of cortical steroids, epidermal wound healing, keloids,hyperkeratotic skin disease, Darier's disease, lamellar ichthyosis,pityriasis rubra pilaris, lichen planus, refractory rosacea, keratosispalmaris et plantaris, leukoplakia, xeroderma pigmentosum, Kaposi'ssarcoma, AIDS-related Kaposi's sarcoma, systemic Kaposi's sarcoma,cutaneous T-cell lymphoma (CTCL, e.g. mycosis fungoides),hyperproliferative skin diseases (e.g. psoriasis, basal cellcarcinomas), disorders of keratinization and keratosis, neoplasticdiseases, disorders of the sebaceous glands (e.g. acne vulgaris,recalcitrant cystic acne, acne and seborrhoic dermatitis).

Infection-related conditions include, without limitation, herpes simplexinfections and lowered resistance to infections.

Examples of eye conditions include, without limitation, nyctalopia,keratinization, xerophthalmia and Grover's disease.

Examples of bone conditions include, without limitation, bone thickeningand myelodysplastic syndromes.

Examples of tumor and related conditions include, without limitation,benign tumor, breast cancer, colon-rectum cancer, lung or otherrespiratory system cancers, skin cancer, basal cell carcinoma, cervicalcancer, mycosis fungoides, Kaposi's sarcoma, AIDS-related Kaposi'ssarcoma, systemic Kaposi's sarcoma, cutaneous T-cell lymphoma (CTCL),squamous cell skin cancer, second primary tumors, head and neckcarcinoma, ovarian cancer, prostate cancer, and renal cell cancer.

Some examples of the conditions that are treatable by a methodcomprising using a HPP/HPC of a retinoid or retinoid-related compound,or a pharmaceutical composition thereof include, without limitation,Vitamin A deficiency related conditions, infection-related conditions,skin conditions, eye conditions, bone conditions, tumor and relatedconditions, and metabolic disorders (e.g. diabetes such as type 2diabetes).

In certain embodiments, a method of treating a retinoid treatablecondition condition comprises administering to a biological system aHPP/HPC of a retinoid or a retinoid related compound such as retinol(vitamin A), retinal, retiferol, tretinoin (all-trans-retinoic acid,e.g. retinoic acid, Retin-A), isotretinoin, alitretinoin (9-cis-retinoicacid), etretinate, acitretin, tazarotene, bexarotene and Adapalene, acompound having a structure selected from the group consisting ofStructure R1, Structure R2, Structure R3, Structure R4, Structure R5,Structure R6, Structure R7, Structure R8, Structure R9, Structure R10,Structure R11, Structure R12, Structure R13, Structure R14, StructureR15, Structure R16, Structure R17, Structure R18, Structure R19,Structure R20, Structure R21, Structure R22, Structure R23, StructureR24, Structure R25, Structure R26, Structure R27, Structure R28,Structure R29, Structure R30, Structure R31, Structure R32, StructureR33, Structure R34, Structure R35, Structure R36, Structure R37,Structure R38, and Structure R39 as defined supra, and mimics thereof.

In certain embodiments, a method of treating a Vitamin A deficiencyrelated condition comprises administering to a biological system aHPP/HPC of a retinoid or a retinoid related compound, or apharmaceutical composition thereof. In a biological system, retinoidregulates a wide range of processes such as vision, reproduction,metabolism, differentiation, bone development, and pattern formationduring embryogenesis. Vitamin A (retinol) and retinal are in chemicalequilibrium in the body and equivalent antixerophthalmic acitivity.Examples of Vitamin A deficiency related conditions include, withoutlimitation, nyctalopia, keratomalacia, keratinization, dry skin, loweredresistance to infection, decreased growth rate, slow bone development,thickening of bone, diminished production of cortical steroids, andfetal malformations.

In certain embodiments, a method of treating a skin condition comprisesadministering to a biological system a HPP/HPC of a retinoid orretinoid-related compound (e.g. tretinoin, isotretinoin, alitretinoin,targretin, retiferol derivatives, and adapalene), or a pharmaceuticalcomposition thereof. Tretinoin (all-trans-retinoic acid) decreasescohesiveness of follicular epithelial cells with decreased microcomedoformation and stimulates mitotic activity increased turnover offollicular epithelial cells causing extrusion of the comedones.Isotretinoin inhibits sebaceous gland function and keratinization.

In certain embodiments, a method of treating a infection-relatedconditions comprises administering to a biological system a HPP/HPC of aretinoids or a retinoid-related compound (e.g. isotretinoin), or apharmaceutical composition thereof.

In certain embodiments, a method of treating a bone condition comprisesadministering to a biological system a HPP/HPC of a retinoids or aretinoid-related compound (e.g. alitretinoin), or a pharmaceuticalcomposition thereof.

In certain embodiments, a method of treating a tumor and relatedconditions comprises administering to a biological system a HPP/HPC of aretinoids or a retinoid-related compound (e.g. isotretinoin, targretin,bexaroten, Targretin®, acyclic retiniods), or a pharmaceuticalcomposition thereof.

In certain embodiments, a method of treating a condition in a subjectamelioratable or treatable with retinoids or retinoid-related compoundscomprises administering a therapeutic effective amount of a HPP of aretinoid or retinoid-related compound, or a pharmaceutical compositionthereof to the subject.

A HPP or a pharmaceutical composition thereof can be administered to abiological system by any administration route known in the art,including without limitation, oral, enteral, buccal, nasal, topical,rectal, vaginal, aerosol, transmucosal, epidermal, transdermal, dermal,ophthalmic, pulmonary, subcutaneous, and/or parenteral administration.The pharmaceutical compositions can be administered in a variety of unitdosage forms depending upon the method of administration.

A parenteral administration refers to an administration route thattypically relates to injection which includes but is not limited tointravenous, intramuscular, intraarterial, intrathecal, intracapsular,intraorbital, intra cardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular,subarachnoid, intraspinal, and/or intrasternal injection and/orinfusion.

A HPP or a pharmaceutical composition thereof can be given to a subjectin the form of formulations or preparations suitable for eachadministration route. The formulations useful in the methods of theinvention include one or more HPPs, one or more pharmaceuticallyacceptable carriers therefor, and optionally other therapeuticingredients. The formulations may conveniently be presented in unitdosage form and may be prepared by any methods well known in the art ofpharmacy. The amount of active ingredient which can be combined with acarrier material to produce a single dosage form will vary dependingupon the subject being treated and the particular mode ofadministration. The amount of a HPP which can be combined with a carriermaterial to produce a pharmaceutically effective dose will generally bethat amount of a HPP which produces a therapeutic effect. In certainembodiments, out of one hundred percent, the amount of HPP/HPC rangesfrom about 0.01 percent to about ninety-nine percent of the HPP. Incertain embodiments, the amount of HPP/HPC ranges from about 0.1 percentto about 20 percent. In certain embodiments, the amount of HPP/HPCrangesfrin about 1 percent to about 5 percent.

Methods of preparing these formulations or compositions include the stepof bringing into association a HPP with one or more pharmaceuticallyacceptable carriers and, optionally, one or more accessory ingredients.In general, the formulations are prepared by uniformly and intimatelybringing into association a HPP with liquid carriers, or finely dividedsolid carriers, or both, and then, if necessary, shaping the product.

Formulations suitable for oral administration may be in the form ofcapsules, cachets, pills, tablets, lozenges (using a flavored basis,usually sucrose and acacia or tragacanth), powders, granules, or as asolution or a suspension in an aqueous or nonaqueous liquid, or as anoil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup,or as pastilles (using an inert base, such as gelatin and glycerin, orsucrose and acacia) and/or as mouth washes and the like, each containinga predetermined amount of a HPP as an active ingredient. A compound mayalso be administered as a bolus, electuary, or paste.

In solid dosage forms for oral administration (e. g., capsules, tablets,pills, dragees, powders, granules and the like), the HPP is mixed withone or more pharmaceutically-acceptable carriers, such as sodium citrateor dicalcium phosphate, and/or any of the following: (1) fillers orextenders, such as starches, lactose, sucrose, glucose, mannitol, and/orsilicic acid; (2) binders, such as, for example, carboxymethylcellulose,alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3)humectants, such as glycerol; (4) disintegrating agents, such asagar-agar, calcium carbonate, potato or tapioca starch, alginic acid,certain silicates, and sodium carbonate, (5) solution retarding agents,such as paraffin, (6) absorption accelerators, such as quaternaryammonium compounds; (7) wetting agents, such as, for example, acetylalcohol and glycerol monostearate; (8) absorbents, such as kaolin andbentonite clay; (9) lubricants, such a talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, andmixtures thereof; and (10) coloring agents. In the case of capsules,tablets and pills, the pharmaceutical compositions may also comprisebuffering agents. Solid compositions of a similar type may also beemployed as fillers in soft and hard-filled gelatin capsules using suchexcipients as lactose or milk sugars, as well as high molecular weightpolyethylene glycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the powdered retinoids orpeptidomimetic moistened with an inert liquid diluent. Tablets, andother solid dosage forms, such as dragees, capsules, pills and granules,may optionally be scored or prepared with coatings and shells, such asenteric coatings and other coatings well known in thepharmaceutical-formulating art. They may also be formulated so as toprovide slow or controlled release of a HPP therein using, for example,hydroxypropylmethyl cellulose in varying proportions to provide thedesired release profile, other polymer matrices, liposomes and/ormicrospheres. They may be sterilized by, for example, filtration througha bacteria-retaining filter, or by incorporating sterilizing agents inthe form of sterile solid compositions which can be dissolved in sterilewater, or some other sterile injectable medium immediately before use.These compositions may also optionally contain pacifying agents and maybe of a composition that they release the HPP(s) only, orpreferentially, in a certain portion of the gastrointestinal tract,optionally, in a delayed manner. Examples of embedding compositionswhich can be used include polymeric substances and waxes. The HPP canalso be in micro-encapsulated form, if appropriate, with one or more ofthe above-described excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the HPP, the liquid dosage forms may containinert diluents commonly used in the art, such as, for example, water orother solvents, solubilizing agents and emulsifiers, such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils(in particular, cottonseed, groundnut, corn, germ, olive, castor andsesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycolsand fatty acid esters of sorbitan, and mixtures thereof. Besides inertdiluents, the oral compositions can also include adjuvants such aswetting agents, emulsifying and suspending agents, sweetening,flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the HPP, may contain suspending agents as,for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitoland sorbitan esters, microcrystalline cellulose, aluminum metahydroxide,bentonite, agar-agar and tragacanth, and mixtures thereof.

Formulations for rectal or vaginal administration may be presented as asuppository, which may be prepared by mixing one or more HPPs with oneor more suitable nonirritating excipients or carriers comprising, forexample, cocoa butter, polyethylene glycol, a suppository wax or asalicylate, and which is solid at room temperature, but liquid at bodytemperature and, therefore, will melt in the rectum or vaginal cavityand release the active agent. Formulations which are suitable forvaginal administration also include pessaries, tampons, creams, gels,pastes, foams or spray formulations containing such carriers as areknown in the art to be appropriate.

Formulations for the topical or transdermal or epidermal or dermaladministration of a HPP composition include powders, sprays, ointments,pastes, creams, lotions, gels, solutions, patches and inhalants. Theactive component may be mixed under sterile conditions with apharmaceutically acceptable carrier, and with any preservatives,buffers, or propellants which may be required. The ointments, pastes,creams and gels may contain, in addition to the HPP composition,excipients, such as animal and vegetable fats, oils, waxes, paraffins,starch, tragacanth, cellulose derivatives, polyethylene glycols,silicones, bentonites, silicic acid, talc and zinc oxide, or mixturesthereof. Powders and sprays can contain, in addition to the HPPcomposition, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants, suchas chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons,such as butane and propane.

A HPP or a pharmaceutical composition thereof can be alternativelyadministered by aerosol. This can be accomplished by preparing anaqueous aerosol, liposomal preparation or solid particles containing theHPPs. A nonaqueous (e. g., fluorocarbon propellant) suspension could beused. Sonic nebulizers can also be used. An aqueous aerosol is made byformulating an aqueous solution or suspension of the agent together withconventional pharmaceutically acceptable carriers and stabilizers. Thecarriers and stabilizers vary with the requirements of the particularcompound, but typically include nonionic surfactants (Tweens, Pluronics,or polyethylene glycol), innocuous proteins like serum albumin, sorbitanesters, oleic acid, lecithin, amino acids such as glycine, buffers,salts, sugars or sugar alcohols. Aerosols generally are prepared fromisotonic solutions.

Transdermal patches can also be used to deliver HPP compositions to atumor site. Such formulations can be made by dissolving or dispersingthe agent in the proper medium. Absorption enhancers can also be used toincrease the flux of the peptidomimetic across the skin. The rate ofsuch flux can be controlled by either providing a rate controllingmembrane or dispersing the peptidomimetic in a polymer matrix or gel.

Ophthalmic formulations, eye ointments, powders, solutions and the like,are also contemplated as being within the scope of this invention.

Formulations suitable for parenteral administration comprise a HPP incombination with one or more pharmaceutically-acceptable sterileisotonic aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, or sterile powders which may be reconstituted into sterileinjectable solutions or dispersions just prior to use, which may containantioxidants, buffers, bacterostats, solutes which render theformulation isotonic with the blood of the intended recipient orsuspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers which may beemployed in the formulations suitable for parenteral administrationinclude water, ethanol, polyols (e. g., such as glycerol, propyleneglycol, polyethylene glycol, and the like), and suitable mixturesthereof, vegetable oils, such as olive oil, and injectable organicesters, such as ethyl oleate. Proper fluidity can be maintained, forexample, by the use of coating materials, such as lecithin, by themaintenance of the required particle size in the case of dispersions,and by the use of surfactants.

Formulations suitable for parenteral administration may also containadjuvants such as preservatives, wetting agents, emulsifying agents anddispersing agents. Prevention of the action of microorganisms may beensured by the inclusion of various antibacterial and antifungal agents,for example, paraben, chlorobutanol, phenol sorbic acid, and the like.It may also be desirable to include isotonic agents, such as sugars,sodium chloride, and the like into the compositions. In addition,prolonged absorption of the injectable pharmaceutical form may bebrought about by the inclusion of agents which delay absorption such asaluminum monostearate and gelatin.

Injectable depot forms are made by forming microencapsule matrices of aHPP or in biodegradable polymers such as polylactide-polyglycolide.Depending on the ratio of the HPP to polymer, and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly (orthoesters) andpoly (anhydrides). Depot injectable formulations are also prepared byentrapping the HPP in liposomes or microemulsions which are compatiblewith body tissue.

In certain embodiments, a HPP of a retinoid or retinoid-relatedcompound, or a pharmaceutical composition thereof is delivered to adisease or tumor site in a therapeutically effective dose. As is knownin the art of pharmacology, the precise amount of the pharmaceuticallyeffective dose of a HPP that will yield the most effective results interms of efficacy of treatment in a given patient will depend upon, forexample, the activity, the particular nature, pharmacokinetics,pharmacodynamics, and bioavailability of a particular HPP, physiologicalcondition of the subject (including race, age, sex, weight, diet,disease type and stage, general physical condition, responsiveness to agiven dosage and type of medication), the nature of pharmaceuticallyacceptable carriers in a formulation, the route and frequency ofadministration being used, and the severity or propensity of a diseasecaused by pathogenic target microbial organisms, to name a few. However,the above guidelines can be used as the basis for fine-tuning thetreatment, e. g., determining the optimum dose of administration, whichwill require no more than routine experimentation consisting ofmonitoring the subject and adjusting the dosage. Remington: The Scienceand Practice of Pharmacy (Gennaro ed. 20.sup.th edition, Williams &Wilkins PA, USA) (2000).

IV. Advantages

Retinoids and related compounds are often too lipophilic and penetratethe skin membrane barrier very slowly. When retinoids are taken orally,retinoids and related compounds are rapidly metabolizeded by enzymes. Inthe case of injection, administration of retinoids is painful and inmany cases requires frequent and costly office visits to treat chronicconditions.

In certain embodiments, since a HPP of the invention is capable ofcrossing one or more biological barriers, the HPP can be administeredlocally (e.g., topically or transdermally) to reach a location where acondition occurs without the necessity of a systematic administration(e.g., oral or parenteral administration). A local administration andpenetration of a HPP allows the HPP to reach the same level of localconcentration of an agent or drug with much less amount or dosage of HPPin comparison to a systematic administration of a parent agent or drug;alternatively, a higher level of local concentration which may not beafforded in the systematic administration, or if possible, requiressignificantly higher dosage of an agent in the systematicadministration. The high local concentration of the HPP or its parentagent if being cleaved enables the treatment of a condition moreeffectively or much faster than a systematically delivered parent agentand the treatment of new conditions that may not be possible or observedbefore. The local administration of the HPP may allow a biologicalsubject to reduce potential sufferings from a systemic administration,e.g., adverse reactions associated with the systematic exposure to theagent, gastrointestinal/renal effects. Additionally, the localadministration may allow the HPP to cross a plurality of biologicalbarriers and reach systematically through, for example, generalcirculation and thus avoid the needs for systematic administration(e.g., injection) and obviate the pain associated with the parenteralinjection.

In certain embodiments, a HPP or a pharmaceutical composition accordingto the invention can be administered systematically (e.g., orally orparenterally). The HPP or the active agent (e.g., drug or metabolite) ofthe HPP may enter the general circulation with a faster rate than theparent agent and gain faster access to the action site a condition.Additionally, the HPP can cross a biological barrier (e.g., blood brainbarrier) which has not been penetrated if a parent agent is administeredalone and thus offer novel treatment of conditions that may not bepossible or observed before.

For example, HPPs of retinoids or retinoid-related compounds in theinvention demonstrated high penetration rate through a biologicalbarrier (e.g., >about 10 times, >about 50 times, >about 100times, >about 200 times, >about 300 times, >about 1000 times higher thanif the retinoids or retinoid-related compounds are administered alone).No or few adverse side effect was observed from the subjects that tookretinoids HPP, while side effects (such as nausea, hair loss, andincreased susceptibility to infection) were observed from the subjectsthat took the parent retinoids at the similar dosage.

V. Examples

The following examples are provided to better illustrate the claimedinvention and are not to be interpreted in any way as limiting the scopeof the invention. All specific compositions, materials, and methodsdescribed below, in whole or in part, fall within the scope of theinvention. These specific compositions, materials, and methods are notintended to limit the invention, but merely to illustrate specificembodiments falling within the scope of the invention. One skilled inthe art may develop equivalent compositions, materials, and methodswithout the exercise of inventive capacity and without departing fromthe scope of the invention. It will be understood that many variationscan be made in the procedures herein described while still remainingwithin the bounds of the invention. It is the intention of the inventorsthat such variations are included within the scope of the invention.

Example 1 Preparation of a HPP from a Parent Drug

Preparation of a HPP from a Parent Drug which Contains at Least OneCarboxylic Group.

In certain embodiments, a parent compound having Structure F-C:

-   -   is converted to a HPP having Structure L-1:

-   -   including stereoisomers and pharmaceutically acceptable salts        thereof, wherein:

F, L₁, L₂, and L₄ are defined as supra;

T is a transportational unit of a HPP of a retinoid or retinoid-relatedcompound. For example, T is selected from the group consisting ofStructure Na, Structure Nb, Structure Nc, Structure Nd, Structure Ne,Structure Nf, Structure Ng, Structure Nh, Structure Ni, Structure Nj,Structure Nk, Structure Nl, Structure Nm, Structure Nn, Structure No,Structure Np, Structure Nq and Structure Nr as defined supra; and

In certain embodiments of the invention, a HPP having Structure L-1 isprepared according to organic synthesis by reacting the parent compoundsor derivatives of the parent compounds having Structure D (e.g. acidhalides, mixed anhydrides of the parent compounds, etc.):

with compounds of Structure E (Scheme 1):

T-L₂-H

Structure E

wherein W₁ is selected from the group consisting of OH, halogen,alkoxycarbonyl and substituted aryloxycarbonyloxy; and

F, L₁, L₂, L₄, and T are defined as supra.

Scheme 1. Preparation of a HPP from a Parent Compound (I).

In certain embodiments of the invention, a HPP having Structure L-1 isprepared according to organic synthesis by reacting a salt of parentcompounds or derivatives of the parent compounds having Structure G(e.g. sodium salt, potassium salt, triethylamine salt, or polymer bondorganic or inorganic base salt, etc.):

Structure G

with compounds of Structure H (Scheme 2):

T-L₂-W₂.HA

Structure H

wherein W₂ is selected from the group consisting of p-toluenesulphonyl,halogen, alkoxycarbonyl and substituted aryloxycarbonyloxy; and

F, L₁, L₂, L₄, and T are defined the same as supra.

Scheme 2. Preparation of a HPP from a Parent Compound (II).

In certain embodiments, a HPP having Structure L-1 is prepared followingScheme 2 as described supra, wherein L₄ is 0=0.

Preparation of N,N-diethylaminoethyl 9-cis-retinoate.HBr

30 g (0.1 mol) of sodium 9-cis-retinoate was dissolved in 100 ml ofacetonitrile. 26.1 g (0.1 mol) of 2-Bromo-N,N-diethylethylamine.HBr wasadded into the reaction mixture. The mixture was stirred for overnightat RT. The solvents were evaporated off. 200 ml of ethanol was addedinto the residue. The solid was removed by filtration. The solution wasevaporated to dryness. 100 ml of ethyl acetate was added into thereaction mixture. Hexane (100 ml) was added. The solid product wascollected by filtration. After drying, it yielded 36 g of the desiredproduct (75%). Hygroscopic product; solubility in water: 30 mg/ml;elementary analysis: C₂₆H₄₂BrNO₂; MW, 480.52; calculated % C, 64.99; H,8.81; Br, 16.63; N, 2.91; O, 6.66. found % C, 65.03; H, 8.80; Br, 16.60;N, 2.89; O, 6.68.

Preparation of N,N-diethylaminoethyl 13-cis-retinoate.HBr

30 g (0.1 mol) of sodium 13-cis-retinoate was dissolved in 100 ml ofacetonitrile. 26.1 g (0.1 mol) of 2-Bromo-N,N-diethylethylamine.HBr wasadded into the reaction mixture. The mixture was stirred for overnightat RT. The solvents were evaporated off. 200 ml of ethanol was addedinto the residue. The solid was removed by filtration. The solution wasevaporated to dryness. 100 ml of ethyl acetate was added into thereaction mixture. Hexane (100 ml) was added. The solid product wascollected by filtration. After drying, it yielded 36 g of the desiredproduct (75%). Hygroscopic product; solubility in water: 30 mg/ml;elementary analysis: C₂₆H₄₂BrNO₂; MW, 480.52; calculated % C, 64.99; H,8.81; Br, 16.63; N, 2.91; O, 6.66. found % C, 65.03; H, 8.80; Br, 16.59;N, 2.88; O, 6.70.

Preparation of N,N-diethylaminoethyl all-trans-retinoate.HBr

30 g (0.1 mol) of sodium all-trans-retinoate was dissolved in 100 ml ofacetonitrile. 26.1 g (0.1 mol) of 2-Bromo-N,N-diethylethylamine.HBr wasadded into the reaction mixture. The mixture was stirred for overnightat RT. The solvents were evaporated off. 200 ml of ethanol was addedinto the residue. The solid was removed by filtration. The solution wasevaporated to dryness. 100 ml of ethyl acetate was added into thereaction mixture. Hexane (100 ml) was added. The solid product wascollected by filtration. After drying, it yielded 35 g of the desiredproduct (72.9%). Hygroscopic product; elementary analysis: C H BrNO; MW,480.52; calculated % C, 64.99; H, 8.81; Br, 16.63; N, 2.91; O, 6.66.found % C, 65.03; H, 8.80; Br, 16.60; N, 2.89; O: 6.68.

Preparation of retinyl N,N-dimethyl-2-aminoacetate.HCl

28.6 g (0.1 mol) of retinol was dissolved in 300 ml of acetonitril. 25ml of triethylamine was added into the reaction mixture. 16 g ofN,N-dimethylaminoacetyl chloride hydrochloride was added into thereaction mixture. The mixture was stirred for 5 h at RT. The solid wasremoved by filtration. The solution was evaporated to dryness. 500 ml ofethyl acetate was added into the residue. 200 ml of 5% of sodiumcarbonate solution was added into the mixture with stirring. The organicsolution was collected and washed with water. After drying, it yielded31 g of the desired product (75.5%). Hygroscopic product; elementaryanalysis: C H CINO; MW, 408.02; calculated % C, 70.65; H, 9.39; Cl:8.69; N, 3.43; O, 7.84. found % Q70.60; H, 9.46; Cl: 8.71; N, 3.42; O:7.81.

Preparation ofN,N-diethylaminoethyl4-[I-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)ethenyl]benzoate.HCl

34.9 g (0.1 mol) of4-[I-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) ethenyl]benzoic acid (bexarotene, Targretin®) was dissolved in 300 ml ofchloroform. 20.6 g of N, N′-Dicyclohexylcarbodiimide was added into thereaction mixture. 11.6 g of dimethylaminoethanol was added into thereaction mixture. The mixture was stirred for 3 hours at RT. The solidwas removed by filtration. The chloroform solution was washed with 5%NaHCO (2×100 ml) and water (3×100 ml). The organic solution was driedover anhydrous sodium sulfate. Sodium sulfate was removed by filtration.3.6 g of HCl gas in ether (100 ml) was added into the reaction mixturewith stirring. The solid product was collected by filtration. Afterdrying, it yielded 40 g of the desired product (85.8%). Hygroscopicproduct; elementary analysis: C H CINO; MW, 484.11; calculated % C,74.43; H, 8.74; Cl: 30 42 27.32; N, 2.89; O, 6.61. found % C, 74.39; H,8.76; Cl: 7.29; N, 2.91, O: 6.65.

Example 2 HPPs of Retinoids and Retinoid-Related Compounds have HigherIn Vitro Penetration Rates Across Human Skin Comparing to their ParentDrugs

Penetration rates of HPPs and their parent drugs through human skin weremeasured in vitro by modified Franz cells. A Franz cell had twochambers, the top sample chamber and the bottom receiving chamber. Thehuman skin tissue (360-400 μm thick) that separated the top and thereceiving chambers was isolated from the anterior or posterior thighareas.

A compound tested (0.2 mL, 5% in 0.2 M phosphate buffer, pH 7.4) wereadded to the sample chamber of a Franz cell. The receiving chambercontains 2 ml of 2% bovine serum albumin in saline which was stirred at600 rpm. The amount of the tested compound penetrating the skin wasdetermined by high-performance liquid chromatography (HPLC) method. Theresults were shown in FIG. 1. The apparent flux values of the testedcompounds were calculated from the slopes in the FIG. 1 and summarizedin Tables 1.

Because the lowest detectable apparent flux values in this method was 1μg/cm²/h, parent drugs that showed a apparent flux value equal to orless than 1 μg/cm²/h were considered as not detectable for penetratingacross the skin tissue. The apparent flux values of these parent drugs(e.g. bexaroten (Targretin®)) were 1 μg/cm²/h, therefore they were notdetectable for penetrating across the skin tissue. However, their HPPshad detectable apparent flux value (0.35 mg/cm²/h for HPP of bexaroten.)For the parents drugs that had a detectable apparent flux value, theirHPPs have a higher detectable apparent flux values respectively.Therefore the HPPs of retinoids or retinoid-related compounds showed ahigher penetration rate across the skin tissue comparing to their parentcompounds.

TABLE 1 In vitro Penetration Rate of HPPs and their Parent Compounds mg/Parent mg/ HPPs cm²/h compounds cm²/h 9-cis-retinoic acid1-piperidineethyl 0.67 9-cis-retinoic 0.005 ester•HBr acid(alitretinoin) N,N-diethylaminoethyl 0.85 13-cis-retinoic 0.00513-cis-retinoate•HBr acid (isotretinoin) N,N-diethylaminoethyl 1.25all-trans-retinoic 0.005 all-trans-retinoate•HBr acid (tretinoin)retinyl N,N-dimethyl-2- 1.21 vitamin A 0.005 aminoacetate•HCl (retinol)N,N-diethylaminoethyl 4-[1-(5,6,7,8- 0.35 bexaroten 0.001tetrahydro-3,5,5,8,8-pentamethyl-2- (Targretin ®)naphthalenyl)ethenyl]benzoate•HCl

Example 3 Irritative Effect or Discomfort of the HPP or HPC on Skin ofMice

Irritative effect or discomfort in the skin of mice of HPPs of retinoidsor retinoid-related compounds was evaluated during a period of 1 weekafter the topical application of 0.1 ml of 0.5% of the respective testdrug in pH 7.4 phosphate buffer (0.2 M) to the back of nude mice twiceper day. None of any signs of irritative effect or discomfort wasobserved for N,N-diethylaminoethyl 9-cis-retinoate.HBr (5% solution, A),N,N-diethylaminoethyl 13-cis-retinoate.HBr (5% solution, B),N,N-diethylaminoethyl all-trans-retinoate.HBr (5% solution, C), retinylN,N-dimethyl-2-aminoacetate.HCl (5% solution, D), orN,N-diethylaminoethyl4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)ethenyl]benzoate.HCl.

Example 4 Conversion of HPPs to their Parent Drugs

HPPs of retinoids or retinoid-related compounds converted to the parentretinoids or retinoid-related compounds quickly in good yield in humanplasma.

A HPP of retinoids or retinoid-related compound (10 mg) was dissolved in0.1 ml of 0.2M pH 7.4 phosphate buffer. 1 ml of human plasma, preheatedto 37° C., was added into the mixture. The mixture was kept in a waterbath at 37° C., and at every 2 min intervals 0.2 ml of samples werewithdrawn and added to 0.4 ml of methanol to precipitate the plasmaprotein. The samples were centrifuged for 5 min and analyzed by HPLC.The results showed that most of the HPPs of retinoids orretinoid-related compounds were converted back to the parent retinoidsor retinoid-related compounds (Table 2).

TABLE 2 Half life of HPPs in plasma Parent Half life HPP drug (min)N,N-diethylaminoethyl 9-cis-retinoate•HBr 12 +/− 1 N,N-diethylaminoethyl13-cis-retinoate•HBr 13 +/− 1 N,N-diethylaminoethyl 11 +/− 1all-trans-retinoate•HBr retinyl N,N-dimethyl-2-aminoacetate•HCl 20 +/− 1N,N-diethylaminoethyl 4-[1-(5,6,7,8- 15 +/− 1tetrahydro-3,5,5,8,8-pentamethyl-2- naphthalenyl)ethenyl]benzoate•HCl

Example 5 Treatment of Clinical Mastitis Using HPPs of Retinoids orRelated Compounds

Without being bounded by any theory, it is believed that Targretin(bexarotene) selectively activates a subclass of retinoid receptorscalled RXRs, which play an important role in several cellularactivities. One of the most important of these activities is calledprogrammed cell death, or “apoptosis,” a natural process by which thebody rids itself of unwanted cells. Targretin is being developed byLigand in both topical and oral formulations. Topical Targretin is usedfor the treatment of cutaneous T-cell lymphoma (CTCL). In addition,Targretin oral formulation is used for the treatment of CTCL, head andneck carcinoma, systemic Kaposi's sarcoma, lung cancer, ovarian cancer,prostate cancer, and renal cell cancer.

Without being bounded by any theory, it is believed that alitretinoin(9-cis-retinoic acid) is a naturally-occurring endogenous retinoid thatbinds to and activates all known intracellular retinoid receptorsubtypes (RARa, RARb, RARg, RXRa, RXRb and RXRg). Once activated thesereceptors function as transcription factors that regulate the expressionof genes that control the process of cellular differentiation andproliferation in both normal and neoplastic cells. Alitretinoid is usedfor treatment of Kaposi's Sarcoma, AIDS-Related Kaposi's Sarcoma, otherskin cancer, breast cancer, and other cancers.

For evaluation of antitumor activity, a human acute promyelocyticleukemia(APL) line derived from a patient with acute promyelocyticleukemia (APL) was implanted into mice. The experiment was carried outon 13 groups of mice: control group (A, administered orally with 0.1 mlof ethanol), groups administered with all-trans-retinoic acid (5 mg/kgor 10 mg/kg in 0.1 ml of ethanol, B₁ or B₂ respectively, orally), groupsadministered with all-trans-retinoic acid 1-piperidineethyl ester.HBr (5mg/kg or 10 mg/kg in 0.1 ml of ethanol, C₁ or C₂ respectively,transdermally), groups administered with 9-cis-retinoic acid (5 mg/kg or10 mg/kg in 0.1 ml of ethanol, D₁ or D₂ respectively, orally), groupsadministered with 9-cis-retinoic acid 2-pyrrolidinemethyl ester.HBr (5mg/kg or 10 mg/kg in 0.1 ml of ethanol, E₁ and E₂ respectively,transdermally), groups administered with bexaroten (5 mg/kg or 10 mg/kgin 0.1 ml of ethanol, F₁ or F₂ respectively, orally), and groupsadministered with4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)ethenyl]benzoicacid 1-pyrrolidinemethyl ester.HCl (5 mg/kg or 10 mg/kg in 0.1 ml ofethanol, G₁ and G₂ respectively, transdermally). The results showed thatthe prodrugs of retinoids demonstrated strong antitumor activity at aslow as 5 mg/kg dose when they were administered transdermally (Table 3).

TABLE 3 Extension of survival period of acute promyelocytic leukemiamice by use of retinoids and their novel prodrugs. None Dose SurvivalLife Disease Com- (mg/kg) Period Elongation Rate at pounds perday n(days) Rate(%) day 160 Control (A) — 7 31.5 ± 2.9 100 0/7 B₁  5 mg 749.7 ± 3.6 158 0/7 B₂ 10 mg 7 78.5 ± 3.7 249 2/7 C₁  5 mg 7 87.8 ± 3.4278 4/7 C₂ 10 mg 7 135.2 ± 5.9  429 5/7 D₁  5 mg 7 45.5 ± 2.3 144 1/7 D₂10 mg 7 65.2 ± 4.1 207 3/7 E₁  5 mg 7 72.5 ± 4.6 230 3/7 E₂ 10 mg 7121.2 ± 4.8  385 5/7 F₁  5 mg 7 64.5 ± 3.7 205 3/7 F₂ 10 mg 7 95.2 ± 3.9302 5/7 G₁  5 mg 7 96.5 ± 4.4 306 5/7 G₂ 10 mg 7 166.5 ± 5.4  529 6/7

Example 6 Antitumor Activity of HPP/HPC of Retinoid or Retinoid-RelatedCompound

For evaluation of antitumor activity of these prodrugs, human breastcancer cells (BCAP-37) were implanted into nude mice (BALB). After 3days, 50 μl of 1% N,N-diethylaminoethyl 9-cis-retinoate.HBr andN,N-diethylaminoethyl4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)ethenyl]benzoate.HClin 0.2M pH 7.4 phosphate buffer were topically applied to human breastcancer cells-implanted area (near the front leg) twice perday. After 20days, the control group demonstrated 100% incidence (the average tumorsize was 10 cm×10 cm), but none of tumor was seen in the test groupsthat treated with N,N-diethylaminoethyl 9-cis-retinoate.HBr orN,N-diethylaminoethyl4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)ethenyl]benzoate.HCl.Mice that were given the drugs did not show any discomfort or irritativeeffect. The average weight of the treated group was 25 grams and that ofthe control group was 21 grams. These prodrugs showed mild side effects.

In the third anti-tumor experiment, human colon cancer cells (LS174J,2-3 mm³ of tumor tissue was used in each mouse) were subcutaneouslyxenografted into nude mice (BALB). After 10 days, the tumors grew to thesize of 55 mm³ (0.055 ml). The experiment was carried out on 4 groups ofmice: control group administered with ethanol (0.1 ml of ethanol, A,transdermally), group administered with all-trans-retinoic acid1-piperidineethyl ester.HBr (10 mg/kg in 0.1 ml of ethanol, B,transdermally), group administered with 9-cis-retinoic acid2-pyrrolidinemethyl ester.HBr (10 mg/kg in 0.1 ml of ethanol, C,transdermally), and group administered with4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)ethenyl]benzoicacid 1-pyrrolidinemethyl ester.HCl (10 mg/kg in 0.1 ml of ethanol, D,transdermally). The results showed that the pro-drugs of retinoids havevery strong anti-tumor activity (Table 4).

TABLE 4 Anti-colon cancer activity of retinoids and their novelprodrugs. Tumor Tumor size at Dose Survival Life size at Com- day 10(mg/kg) Period Elongation day 40 pounds (mm³) perday n (days) Rate(%)(mm³) A 52 ± 15  0 mg 7 50.5 ± 5.2 100 1255 ± 65  B 55 ± 13 10 mg 7 85.7± 7.6 170 675 ± 55 C 57 ± 19 10 mg 7 81.5 ± 5.7 161 627 ± 49 D 56 ± 1 10 mg 7 105.7 ± 5.8  209 487 ± 61

Example 7 Treatment of Psoriasis Using HPPs of Retinoids orRetinoid-Related Compounds

Heavy suspensions of Malassezia [Rosenberg, E. W., et al.,Mycopathologia, 72, 147-154 (1980)] were applied to shaved skin on thebacks of Chinese white rabbits (n=4×10) twice (at 7 am and 7 μmrespectively) per day for 2 weeks. Lesions similar to psoriasisresulted. Then the same dosage of Malassezia was applied to the samearea with a 0.5% aqueous solution of 200 μl of 0.05%N,N-diethylaminoethyl 9-cis-retinoate.HBr or all-trans-retinoic acid1-piperidineethyl ester.HBr being applied to the same areas 3 hours (10am and 10 pm) after the application of Malassezia (7 am and 7 pm). Thecontrol group was only applied with Malassezia. 10 days after theapplication of both the Malassezia and the HPPs, the lesions of thegroups that were treated with HPPs were resolved, and the lesions in thecontrol groups became worse.

Example 8 Treatment of Acute Promyelocytic Leukemia

5 ml of 1% N,N-diethylaminoethyl 9-cis-retinoate.HCl in 50% ethanol issprayed to skin on chest, back, or any part of the body twice per dayand 10 ml/m² of(8S,10S)-8-acetyl-10-[(2S,4S,5S,6S)-4-amino-5-acetoxy-6-methyl-oxan-2-yl]oxy-6,8,11-triacetoxy-1-methoxy-9,10-dihydro-7H-tetracene-5,12-dione.HCl(tetraacetyl daunorubicin.HCl) is administered in a rapid intravenousinfusion for 30 days or until the disease is cured.

Example 9 Treatment of Breast Cancer

0.5 ml of 2% N,N-diethylaminoethyl4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)ethenyl]benzoate.HClin 50% ethanol is sprayed to skin on the tumor, 1 hour later, 0.5 ml of0.5% (8S,10S)-8-acetyl-10-[(2S,4S,5S,6S)-4-amino-5-acetoxy-6-methyl-oxan-2-yl]oxy-6,8,11-triacetoxy-1-methoxy-9,10-dihydro-7H-tetracene-5,12-dione.HCl(tetraacetyl daunorubicin.HCl) in 50% ethanol is sprayed on the samearea of skin on the tumor. The process is repeated three times per dayand the treatment is continued until the tumor disappeared.

Example 10 Treatment of Prostate Cancer

0.5 ml of 2% N,N-diethylaminoethyl all-trans-retinoate.HCl in 50%ethanol is sprayed to skin on the pubic area, 1 hour later, 0.5 ml of0.5%(8S,10S)-10-(4-amino-5-acetoxy-6-methyl-tetrahydro-2H-pyran-2-yloxy)-6,8,11-triacetoxy-8-(2-acetoxyacetyl)-1-methoxy-7,8,9,10-tetrahydrotetracene-5,12-dione.HCl(pentaacetyl doxorubicin.HCl) in 50% ethanol is sprayed on the same areaof skin on the pubic area. The process is repeated three times per dayand the treatment is continued until the cancer is cured.

Example 11 Treatment of Lung Cancer

0.5 ml of 2% N,N-diethylaminoethyl all-trans-retinoate.HCl in 50%ethanol are sprayed to skin on chest, 1 hour later, 0.5 ml of 0.5%(8S,10S)-10-(4-amino-5-acetoxy-6-methyl-tetrahydro-2H-pyran-2-yloxy)-6,8,11-triacetoxy-8-(2-acetoxyacetyl)-1-methoxy-7,8,9,10-tetrahydrotetracene-5,12-dione.HCl(pentaacetyl doxorubicin.HCl) in 50% ethanol is sprayed on the same areaof skin on the chest. The process is repeated three times per day andthe treatment is continued until the disease is cured.

Example 12 Treatment of Lung Cancer

0.5 ml of 2% N,N-diethylaminoethyl all-trans-retinoate.HCl in 50%ethanol is inhaled into the lung, 1 hour later, 0.5 ml of 0.5%(8S,10S)-10-(4-amino-5-acetoxy-6-methyl-tetrahydro-2H-pyran-2-yloxy)-6,8,11-triacetoxy-8-(2-acetoxyacetyl)-1-methoxy-7,8,9,10-tetrahydrotetracene-5,12-dione.HCl(pentaacetyl doxorubicin.HCl) in 50% ethanol is inhaled to lung. Theprocess is repeated three times per day and the the treatment iscontinued until the disease is cured.

Example 13 Treatment of Skin Cancer

1 ml of 2% N,N-diethylaminoethyl all-trans-retinoate.HCl in 50% ethanolis sprayed to the skin having skin cancer three times per day and thetreatment is continued until the disease is cured.

Example 14 Treatment of Acne Vulgaris

1 ml of 0.5% N,N-diethylaminoethyl all-trans-retinoate.HCl in 50%ethanol is applied to skin with acne vulgaris three times per day andthe treatment is continued until the condition is cured.

Example 15 Treatment of Psoriasis

3 ml of 0.5% N,N-diethylaminoethyl 9-cis-retinoate.HCl in 50% ethanol isapplied to skin with psoriasis three times per day and the treatment iscontinued until the disease is cured.

Example 16 Treatment of the Smoking Disease Emphysema

3 ml of 1% N,N-diethylaminoethyl all-trans-retinoate.HCl in 50% ethanolis applied to the skin on the chest three times per day and thetreatment is continued until the disease is cured.

Example 17 Treatment of the Smoking Disease Emphysema

3 ml of 1% N,N-diethylaminoethyl all-trans-retinoate.HCl in 50% ethanolis inhaled to the lung three times per day and the treatment iscontinued until the disease is cured.

Example 18 Treatment for Severe Lung Disease, Chronic ObstructivePulmonary Disease (COPD)

3 ml of 1% N,N-diethylaminoethyl all-trans-retinoate.HCl in 50% ethanolis applied to skin on the chest three times per day and the treatment iscontinued until the disease is cured.

Example 19 TREATMENT FOR SEVERE LUNG DISEASE, CHRONIC OBSTRUCTIVEPULMONARY DISEASE (COPD)

3 ml of 1% N,N-diethylaminoethyl all-trans-retinoate.HCl in 50% ethanolis inhaled to the lung three times per day and the treatment iscontinued until the disease is cured.

1-20. (canceled)
 21. A high penetration composition of a retinoid or a retinoid-related compound comprising a) a functional unit; b) a linker c) a transportational unit; wherein the functional unit is covalently linked to the transportational unit via the linker; wherein the functional unit comprises a moiety of the retinoids or the retinoid-related compound; wherein the transportational unit comprises a protonatable amine group; and wherein the linker comprises a chemical bond that is capable of being cleaved after the high penetration composition penetrates across a biological barrier.
 22. The high penetration composition according to claim 21, wherein the chemical bond is selected from the group consisting of a covalent chemical bond, an ether bond, a thioether bond, an ester bond, a thioester bond, a carbonate bond, a carbamate bond, a phosphate bond, and an oxime bond.
 23. The high penetration composition according to claim 21, wherein upon cleavage of the cleavable bond, the moiety of the retinoids or the retinoid-related compound is converted to the retinoids or the retinoid-related compound.
 24. The high penetration composition according to claim 21, wherein the functional unit comprises a lipophilic derivative of a moiety of the retinoids or the retinoid-related compound.
 25. The high penetration composition according to claim 24, wherein the lipophilic derivative is selected from the group consisting of carbonate, ester, amide, carbamate, N-mannich base, ether, thioether, thioester, phosphate, oxime and imine.
 26. The high penetration composition according to claim 21 wherein the retinoids or the retinoid-related compound is selected from the group consisting of retinoids, retinoids metabolites, and agents that can be metabolized into a retinoid or a retinoid metabolite, and analogs thereof.
 27. The high penetration composition according to claim 21, wherein the protonatable amine group is selected from the group consisting of a substituted and unsubstituted primary amine group, a substituted and unsubstituted secondary amine group, and a substituted and unsubstituted tertiary amine group.
 28. The high penetration composition according to claim 27, wherein the protonatable amine group is selected from the group consisting of Structure Na, Structure Nb, Structure Nc Structure Nd, Structure Ne, Structure Nf, Structure Ng, Structure Nh, Structure Ni, Structure Nj, Structure Nk, Structure Nl, Structure Nm, Structure Nn, Structure No, Structure Np, Structure Nq, and Structure Nr:

including stereoisomers and pharmaceutically acceptable salts thereof, wherein: R₁₁-R₁₆ are independently selected from the group consisting of nothing, H, CH₂COOR₁₁, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted alkyl halide, wherein any carbon or hydrogen may be further independently replaced with 0, S, P, NR₁₁, or any other pharmaceutically acceptable groups.
 29. A high penetration composition having the following chemical structure:

including stereoisomers and pharmaceutically acceptable salts thereof, wherein: F comprises a moiety of a retinoid or a retinoid-related compound, having a structure selected from the group consisting of Structure F2, Structure F3, Structure F4, Structure F5, Structure F6, Structure F7, Structure F8, Structure F9, Structure F10, Structure F11, Structure F12, Structure F13, Structure F14, Structure F15, Structure F16, Structure F17, Structure F18, Structure F19, Structure F20, Structure F21, Structure F22, Structure F23, Structure F24, Structure F25, Structure F26, Structure F27, Structure F28, Structure F29, Structure F30, Structure F31, Structure F32, Structure F33, Structure F34, Structure F35, Structure F36, Structure F37, Structure F38, Structure F39, Structure F40 and Structure F41:

including stereoisomers and pharmaceutically acceptable salts thereof, wherein: R₁ is selected from the group consisting of H, substituted and unsubstituted alkyl, substituted and unsubstituted alkyloxyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl and substituted and unsubstituted heteroaryl residues; R₂ is selected from the group consisting of H, substituted and unsubstituted alkyl, substituted and unsubstituted alkyloxyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl and substituted and unsubstituted heteroaryl residues; X is selected from the group consisting of 0, S, and NH; X₁-X₈ are independently selected from the group consisting of H, OH, Cl, Br, F, I, substituted and unsubstituted alkyl, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted alkyloxy; R₄ is selected from the group consisting of H, OH, Cl, Br, F, I, substituted and unsubstituted alkyl, substituted and unsubstituted alkyloxy, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted alkyl halide; R₅ is selected from the group consisting of H, OH, Cl, Br, F, I, substituted and unsubstituted alkyl, substituted and unsubstituted alkyloxy, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted alkyl halide; R₂₁ and R₂₂ are independently selected from the group consisting of H, OH, Cl, Br, F, I, substituted and unsubstituted alkyl, substituted and unsubstituted alkyloxy, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted alkyl halide; R₆ and R₆′ taken together is oxygen (═O) or taken alone are the same or different and independently selected from the group consisting of H, Cl, Br, F, I, OH, substituted and unsubstituted alkyl, substituted and unsubstituted alkyloxy, and substituted and unsubstituted alkyl halide; R₇ and R₇′ taken together is oxygen (═O) or taken alone are the same or different and independently selected from the group consisting of H, Cl, Br, F, I, OH, substituted and unsubstituted alkyl, substituted and unsubstituted alkyloxy, and substituted and unsubstituted alkyl halide; R₅ and R₅′ taken together is oxygen (═O) or taken alone are the same or different and independently selected from the group consisting of H, Cl, Br, F, I, OH, substituted and unsubstituted alkyl, substituted and unsubstituted alkyloxy, and substituted and unsubstituted alkyl halide; R₉ and R₉′ taken together is oxygen (═O) or taken alone are the same or different and independently selected from the group consisting of H, Cl, Br, F, I, OH, substituted and unsubstituted alkyl, substituted and unsubstituted alkyloxy, and substituted and unsubstituted alkyl halide; R₁₀ and R₁₀′ taken together is oxygen (═O) or taken alone are the same or different and independently selected from the group consisting of H, Cl, Br, F, I, OH, substituted and unsubstituted alkyl, substituted and unsubstituted alkyloxy, and substituted and unsubstituted alkyl halide; T_(R) is selected from the group consisting of —CH₂═C—, —CH═CH—, —C≡C—, —C(═O)NH—, —C(═S)NH—, —C(═O)O—, —OC(═O)—, —C(═O)S—, —C(═O)CH₂—, and —CH₂C(═O)—; HA is selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, nitric acid, sulfic acid, bisulfic acid, phosphoric acid, phosphorous acid, phosphonic acid, isonicotinic acid, acetic acid, lactic acid, salicylic acid, citric acid, tartaric acid, pantothenic acid, bitartaric acid, ascorbic acid, succinic acid, maleic acid, gentisinic acid, fumaric acid, gluconic acid, glucaronic acid, saccharic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzensulfonic acid, p-toluenesulfonic acid and pamoic acid; any CH₂ groups may be replaced with 0, S, or NH; T is selected from the group consisting of nothing, H, substituted and unsubstituted alkyl, substituted and unsubstituted alkyloxyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, Structure Na, Structure Nb, Structure Nc, Structure Nd, Structure Ne, Structure Nf, Structure Ng, Structure Nh, Structure Ni, Structure Nj, Structure Nk, Structure Nl, Structure Nm, Structure Nn, Structure No, Structure Np, Structure Nq, and Structure Nr:

each R₁₁—R₁₆ is independently selected from the group consisting of nothing, H, CH2COOR₁₁, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted alkyl halide, wherein any carbon or hydrogen may be further independently replaced with 0, S, P, NR₁₁, or any other pharmaceutically acceptable groups; L₁ is selected from the group consisting of nothing, 0, S, —N(L₃)-, —N(L₃)-CH₂—O, —N(L₃)-CH₂—N(L₅)-, —O—CH₂—O—, —O—CH(L₃)-O, —S—CH(L₃)-O—; L₂ is selected from the group consisting of nothing, O, S, —N(L₃)-, —N(L₃)-CH₂—O, —N(L₃)-CH₂—N(L₅)-, —O—CH₂—O—, —O—CH(L₃)-O, —S—CH(L₃)-O—, —O-L₃-, —N-L₃-, —S-L₃- and —N(L₃)-L₅-; L₄ is selected from the group consisting of C═O, C═S,

for each L₁, L₂, L₄, L₃ and L₅ are independently selected from the group consisting of nothing, H, CH₂COOL₆, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted alkyl halide, wherein any carbon or hydrogen may be further independently replaced with O, S, P, NL₃, or any other pharmaceutically acceptable groups; L₆ is selected from the group consisting of H, OH, Cl, F, Br, I, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted alkyl halide, wherein any carbon or hydrogen may be further independently replaced with O, S, N, P(O)OL₇, CH═CH, C≡C, CHL₇, CL₅L₇, aryl, heteroaryl, or cyclic groups; L₇ is selected from the group consisting of H, OH, Cl, F, Br, I, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted alkyl halide, wherein any carbon or hydrogen may be further independently replaced with O, S, N, P(O)OL₆, CH═CH, C≡C, CHL₆, CL₆L₅, aryl, heteroaryl, or cyclic groups.
 30. The high penetration composition of claim 29 wherein the retinoids wherein the retinoids comprise a structure selected from the group consisting of Structure R2, Structure R3, Structure R4, Structure R5, Structure R6, Structure R7, Structure R8, Structure R9, Structure R10, Structure R11, Structure R12, Structure R13, Structure R14, Structure R15, Structure R16, Structure R17, Structure R18, Structure R19, Structure R20, Structure R21, Structure R22, Structure R23, Structure R24, Structure R25, Structure R26, Structure R27, Structure R28, Structure R29, Structure R30, Structure R31, Structure R32, Structure R33, Structure R34, Structure R35, Structure R36, Structure R37, Structure R38, and Structure R39:


31. The high penetration composition of claim 29 comprising a structure selected form the group consisting of Structure 2, Structure 3, Structure 4, Structure 5, Structure 6, Structure 7, Structure 8, Structure 9, Structure 10, Structure 11, Structure 12, Structure 13, Structure 14, Structure 15, Structure 16, Structure 17, Structure 18, Structure 19, Structure 20, Structure 21, Structure 22, Structure 23, Structure 24, Structure 25, Structure 26, Structure 27, Structure 28, Structure 29, Structure 30, Structure 31, Structure 32, Structure 33, Structure 34, Structure 35, Structure 36, Structure 37, Structure 38, and Structure 39:

including stereoisomers and pharmaceutically acceptable salts thereof, wherein: R is selected from the group consisting of nothing, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxyl, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkyl halide, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl.
 32. A pharmaceutical composition comprising a high penetration composition according to claim 29 and a pharmaceutically acceptable carrier.
 33. The pharmaceutical composition according to claim 32, wherein the pharmaceutically acceptable carrier is polar.
 34. The pharmaceutical composition according to claim 32, wherein the pharmaceutically acceptable carrier is selected from the group of alcohol, acetone, ester, water, and aqueous solution.
 35. A method for penetrating a biological barrier, comprising administering to the biological barrier a pharmaceutical composition according to claim
 32. 36. A method for screening a HPP of a retinoid or a retinoid-related compound for a desired character, comprising the following steps: 1) covalently linking a functional unit comprising a retinoid or a retinoid-related compound to a transportational unit through a linker to form a test composition; 2) administering the test composition to a biological subject or a biological barrier; and 3) determining whether the test composition has a desired character.
 37. The method according to claim 36, wherein the desired character is selected from the group consisting of: 1) the ability of the test composition to penetrate the biological barriers; 2) the ability of the test composition to convert to a parent drug or to an active agent; 3) the penetration rate of the test composition; 4) the efficiency of the test composition; and 5) the efficacy of the test composition.
 38. A method for diagnosing a condition in a biological subject, comprising the following steps: 1) administering a composition according to any one of claim 29 to the biological subject; 2) detecting the presence, location or amount of the composition in the biological subject; and 3) detecting a condition in the biological subject.
 39. The method according to claim 38, wherein the composition is labeled.
 40. A method for diagnosing a condition in a biological subject, comprising the following steps: 1) administering a composition according to any one of claim 32 to the biological subject; 2) detecting the presence, location or amount of the composition in the biological subject; and 3) detecting a condition in the biological subject.
 41. The method according to claim 40, wherein the composition is labeled.
 42. A method for treating a condition in a biological subject, comprising administering to the biological subject the high penetration composition according to claim
 29. 43. A method for treating a condition in a biological subject, comprising administering to the biological subject the pharmaceutical composition according to claim
 32. 44. The method according to claim 43, wherein the condition is selected from the group consisting of Vitamin A deficiency conditions, infection-related conditions, skin conditions, eye conditions, bone conditions, tumor and related conditions, hair loss, and metabolic disorders.
 45. The method according to claim 44, wherein the Vitamin A deficiency related condition is selected from the group consisting of nyctalopia, keratomalacia, keratinization, dry skin, lowered resistance to infection, decreased growth rate, slow bone development, thickening of bone, diminished production of cortical steroids, and fetal malformations.
 46. The method according to claim 44, wherein skin condition is selected from the group consisting of keratinization, dry skin, skin damage through sun exposure, photoaging, hyperpigmented macules (liver spot), premature wrinkles, elastosis and premature aging, wrinkles, drug-induced photosensitivity, diminished production of cortical steroids, epidermal wound healing, keloids, hyperkeratotic skin disease, Darier's disease, lamellar ichthyosis, pityriasis rubra pilaris, lichen planus, refractory rosacea, keratosis palmaris et plantaris, leukoplakia, xeroderma pigmentosum, Kaposi's sarcoma, AIDS-related Kaposi's sarcoma, systemic Kaposi's sarcoma, cutaneous T-cell lymphoma (CTCL), Mycosis fungoides, hyperproliferative skin diseases, psoriasis, basal cell carcinomas, disorders of keratinization and keratosis, neoplastic diseases, disorders of the sebaceous glands, acne vulgaris, recalcitrant cystic acne, acne and seborrhoic dermatitis.
 47. The method according to claim 44, wherein the infection-related condition is selected from the group consisting of herpes simplex infections and lowered resistance to infections.
 48. The method according to claim 44, wherein the eye condition is selected from the group consisting of nyctalopia, keratinization, xerophthalmia and Grover's disease.
 49. The method according to claim 44, wherein the bone condition is selected from the group consisting of bone thickening and myelodysplastic syndromes.
 50. The method according to claim 44, wherein the metabolism disorder conditions are selected from the group consisting of diabetes mellitus and type II diabetes.
 51. The method according to claim 44, wherein the tumor is selected from the group consisting of benign tumor, breast cancer, colon-rectum cancer, lung or other respiratory system cancers, skin cancer, basal cell carcinoma, cervical cancer, mycosis fungoides, Kaposi's sarcoma, AIDS-related Kaposi's sarcoma, systemic Kaposi's sarcoma, cutaneous T-cell lymphoma (CTCL), squamous cell skin cancer, second primary tumors, head and neck carcinoma, ovarian cancer, prostate cancer, and renal cell cancer.
 52. The method according to claim 44, wherein the composition is administered to the biological subject through a route selected from oral, enteral, buccal, nasal, topical, rectal, vaginal, aerosol, transmucosal, epidermal, transdermal, dermal, ophthalmic, pulmonary, subcutaneous, and parenteral administration.
 53. The method according to claim 44, wherein the retinoids is selected from the group consisting of retinol (vitamin A), retinal, retiferol, tretinoin (all-trans-retinoic acid), isotretinoin, 13-cis-retinoic acid, alitretinoin (9-cis-retinoic acid), etretinate, acitretin, tazarotene, bexarotene and Adapalene.
 54. The method according to claim 44, wherein the retinoids comprise a structure selected from the group consisting of Structure R2, Structure R3, Structure R4, Structure R5, Structure R6, Structure R7, Structure R8, Structure R9, Structure R10, Structure R11, Structure R12, Structure R13, Structure R14, Structure R15, Structure R16, Structure R17, Structure R18, Structure R19, Structure R20, Structure R21, Structure R22, Structure R23, Structure R24, Structure R25, Structure R26, Structure R27, Structure R28, Structure R29, Structure R30, Structure R31, Structure R32, Structure R33, Structure R34, Structure R35, Structure R36, Structure R37, Structure R38, and Structure R39 as defined in claim
 30. 